Twin-screw dry granulation for producing solid formulations

ABSTRACT

A dry granulation process using a twin-screw extruder for granulating a powder mixture which includes at least one active ingredient and at least one carrier. The process includes steps of kneading the powder mixture in the screw barrel of the twin-screw extruder at a barrel temperature below a melting point of the at least one active ingredient and a melting point or a glass transition temperature of the at least one carrier to provide a kneaded powder mixture, and extruding the kneaded powder mixture to form granules. Granules and tablets produced using the dry granulation process in the twin-screw extruder are also provided.

REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.15/493,568, filed Apr. 21, 2017, which claims the priority of U.S.Provisional Application No. 62/326,046, filed Apr. 22, 2016, the entirecontents of each of which are incorporated herein by reference.

FIELD OF THE DISCLOSURE

The present disclosure relates to a granulation process for producingsolid formulations. In particular, the present disclosure relates to adry granulation process using one or more twin-screw extruders forproducing solid, high-dose formulations or formulations of dehydrationsensitive ingredients.

BACKGROUND OF THE DISCLOSURE

Granulation is a process in which small particles agglomerate intolarger, multi-particle masses called granules. The granulation processis routinely utilized in the pharmaceutical industry for formulatingsolid oral dosage formulations as well as in various other industries.Granulation has several advantages such as reducing dust of fineparticles that may cause potential health and environmental hazards,avoiding segregation of different components in a formulation, producinggranules that are easy to handle and transport, and improvingflowability and compressibility of the ingredients.

Granulation processes can be divided into two types: wet granulation anddry granulation. Wet granulation processes utilize some form of solventor liquid binder to bind small particles together to form agglomerates.Dry granulation processes are carried out without a solvent or liquidbinder. Wet granulation may use any of low-shear mixing, high-shearmixing, extrusion-spheronization, or fluid-bed processing for producingwet granules, which are then dried, sieved, and optionally ground priorto being compressed into tablets (when tableting is desired). Wetgranulation is frequently used in the pharmaceutical industry, but ithas proven to have some disadvantages. In some cases, for example, thesolvent or liquid binder may have an adverse effect on other ingredientsin the formulation and/or on one or more properties of the end product,such as a tablet. Further, the wet granulation process usually requiresa drying step to remove the solvent or liquid binder after granulation.

WO 2012160051 A2 discloses wet granulation methods using differentgranulation solvents such as isopropyl alcohol, dichloromethane,methanol, acetone or mixtures thereof for manufacturing cetyl myristateor cetyl palmitate or a combination of cetyl myristate and cetylpalmitate. Moreover, it is known that selection of an appropriategranulation solvent in an appropriate amount is important forgranulation of waxy materials. The physical and chemical properties ofthe active ingredient(s) also should be considered for the selection ofthe granulation method.

Dry granulation can be employed to overcome some of the disadvantages ofwet granulation that result from the use of a solvent or liquid binder.In a dry granulation process, powdered components, typically in the formof fine particles are mixed prior to granulation and then compressed toyield hard granules which may then be ground and sieved, as necessary,to produce particles of a desired size distribution. In some cases, drygranulation may use either slugging or roller compression to producecompacts, also known as briquettes, flakes or ribbons, which may then bemilled to obtain the desired granules. Unfortunately, it is oftenchallenging to produce granules having the desired properties using drygranulation. Dry granulation processes, as well as known issues relatedto them, are discussed in a review article by Peter Kleinebudde, “Rollcompaction/dry granulation: pharmaceutical applications,” EuropeanJournal of Pharmaceutics and Biopharmaceutics, vol. 58, pages 317-326,(2004).

Roller compaction is a widely used dry granulation method as it does notrequire an additional drying step. This enables robust processes usingsmall equipment. Agglomeration depends mainly on the compactibility ofthe substances, thus high amounts of fines are often produced, which isthe major drawback of the roller compaction process. If a tablet pressis used for the compaction process, the process is termed, “slugging.”However, since particles with a small particle size do not flow wellinto the die of a tablet press, this may result in weight differencesfrom one tablet (slug) to another. This, in turn, causes largefluctuations in the forces applied to the individual slugs, whichtranslates into variations in the mechanical strength of differentslugs. Therefore, the properties of granulates obtained by milling theslugs also may not be controlled to the desired extent. This is one ofthe main reasons why slugging is infrequently used as a dry granulationmethod.

US 2010/0184861 discloses a method for producing granules from a powder,by application of a compaction force on the powder to produce granulescomprising a mixture of fine particles, followed by separating andremoving fine particles and/or small granules from larger granules byentraining the fine particles and/or small granules in a gas stream. Thepowder, which may comprise APIs and/or pharmaceutically acceptablecarriers, is generally composed of fine particles with a mean particlesize of less than 100, 50, or 20 μm. The method may be carried out as acontinuous process in the substantial absence of liquid.

U.S. Pat. No. 8,846,088 discloses a melt granulation process for makinga composition comprising a powder of a calcium-containing compound and asugar alcohol. The process is said to produce granules with a desirabletaste and mouth feel. Heating is applied to the composition duringgranulation to sufficiently melt or soften the sugar alcohol to enableat least partial coverage of the calcium-containing compound particles.The sugar alcohol provides taste masking of the calcium-containingcompound and can also improve mouth feel. The method is especiallysuitable for manufacturing tablets having a high loading of acalcium-containing compound.

U.S. Pat. No. 6,499,984 discloses a single pass, continuous, automatedsystem for producing pharmaceutical granules using a wet granulationprocess. The system includes multiple feeders to feed powders andliquids into the system, a twin-screw processor to granulate thepowders, a radio frequency or microwave based drying apparatus to drythe granules, and at least one mill to process the dried granules todesired particle sizes. The system also includes means for monitoringkey process parameters on-line, which parameters may be controlled by acontroller that provides feedback control to the monitored components inthe system. The produced granules can be compressed into tablets orincorporated as a fill material into capsules. The system producesgranules having consistent properties even when production is scaled-upfor commercial manufacture.

It is known in the art to use twin-screw extruders for granulation usinga wet granulation process. In a twin-screw extruder, the inputmaterials, typically powders and granulation fluid, are introduced intoa screw barrel by a feeder and granules are produced, often by extrusionof the wet mass through a die block, at the exit of the twin-screwextruder. Maniruzzarnan can be prepared by wet granulations of ibuprofenusing hot-melt twin screw extruder using water as a liquid binder.(Maniruzzaman M, Nair A, Renault M, Nandi U, Scoutaris N, Famish R,Bradley M S, Snowden M J, Douroumis D. Continuous twin-screw granulationfor enhancing the dissolution of poorly water soluble drug.International journal of pharmaceutics. 2015 Dec. 30:496(1):52-62).

It is also known in the art to use twin-screw extruders for meltgranulation. (see e.g. Michael R. Thompson “Hot-Melt Granulation in aTwin Screw Extruder: Effects of Processing on Formulations with Caffeineand Ibuprofen” Journal of Pharmaceutical Sciences, Vol. 102, 4330-4336(2013); and Van Melkebeke et al., “Melt granulation using a twin-screwextruder: a case study.” International Journal of Pharmaceutics, (2006)December 1; 326(1), pp. 89-93) investigated the use of a twin screwextruder for melt granulation. Polyethylene glycols (PEG 400 and 4000)were used as meltable binders. During granulation the drug particleswere finely dispersed in the molten mixture, whereby the PEG 400 and4000 created a micro-environment around the drug particles enhancing thedissolution rate.

SUMMARY OF THE DISCLOSURE

The present disclosure is directed to a dry granulation process using atwin-screw extruder. Extrusion using a twin-screw extruder may provideadvantages such as economical processing, a small scale-up footprint,reduced in-process times, and reduced processing steps with continuousoperation. Although it was known in the art to make granules usingtwin-screw extruders using a wet granulation process or a meltgranulation process, Applicants have developed the use of a twin-screwextruder to make granules by a dry granulation process.

The dry granulation process of the present disclosure can be performedwithout solvent or liquid binders. The dry granulation process of thedisclosure can facilitate the handling of sensitive ingredients that maybe subject to dehydration or adversely affected by solvents, excessiveheat, or liquid binders. In some cases, the present disclosure can alsofacilitate the production of high loading granules.

In some embodiments, a method of producing granules includes mixing afirst powder including at least one active ingredient and a secondpowder including at least one carrier to form a powder mixture; feedingthe powder mixture to a twin-screw extruder without a solvent or aliquid binder; kneading the powder mixture in a heated screw barrel ofthe twin-screw extruder, wherein all temperatures along a length of thescrew barrel are below the melting point of the at least one activeingredient and below the melting point or a glass transition temperatureof the at least one carrier to form a kneaded powder mixture; andextruding the kneaded powder mixture to form the granules. In someembodiments, the twin-screw extruder includes two screws that are fullyintermeshing, co-rotating screws. In some embodiments, a barreltemperature at one location along a length of the screw barrel isdifferent from a barrel temperature at another location along the lengthof the screw barrel. In some embodiments, a first zone closest to anoutlet of the screw barrel has a lower barrel temperature than a secondzone at a center portion along the length of the screw barrel. In someembodiments, all temperatures along the length of the screw barrel arebetween 50-100° C. In some embodiments, the twin-screw extruder does nothave a die block for extruding the granules. In some embodiments, thepowder mixture further comprises a lubricant. In some embodiments, thelubricant is added to the powder mixture before kneading the powdermixture. In some embodiments, the powder mixture includes 0.01-1 wt %the powder mixture. In some embodiments, the lubricant is selected fromthe group consisting of magnesium stearate, zinc stearate, lithiumstearate, calcium stearate, aluminum stearate, sodium stearyl fumarate,talc, glyceryl behenate, and colloidal silicon dioxide. In someembodiments, all temperatures along the length of the screw barrel arebelow the melting point or the glass transition temperature of allcomponents in the powder mixture. In some embodiments, the melting pointor the glass transition temperature of the at least one carrier is lowerthan the melting point of the at least one active ingredient. In someembodiments, the powder mixture includes two or more polymeric carriers.In some embodiments, the powder mixture further includes at least one ofa plasticizer, binder, filler, disintegrant, or organic acid. In someembodiments, the powder mixture further includes an organic acid. Insome embodiments, a screw speed of the twin-screw extruder is less than200 rpm. In some embodiments, a feed rate into the twin-screw extruderis less than about 400 g/hr. In some embodiments, the method includespressing the granules into a tablet. In some embodiments, the tablet hasa hardness of 5-20 kp. In some embodiments, the tablet has a friabilityof less than 0.5%.

In some embodiments, a granule is produced by a method including mixinga first powder including at least one active ingredient and a secondpowder including at least one carrier to form a powder mixture; feedingthe powder mixture to a twin-screw extruder without a solvent or aliquid binder; kneading the powder mixture in a heated screw barrel ofthe twin-screw extruder, wherein all temperatures along a length of thescrew barrel are below the melting point of the at least one activeingredient and below the melting point or the glass transitiontemperature of the at least one carrier to form a kneaded powdermixture; and extruding the kneaded powder mixture to form the granule.In some embodiments, a granule includes at least one active ingredientand at least one carrier having a melting point or a glass transitiontemperature lower than the melting point of the at least one activeingredient, wherein the granule has a compressibility index of 10-30 anda Hausner ratio of less than 1.25.

In some embodiments, the at least one active ingredient is selected fromthe group consisting of heat-sensitive active pharmaceuticalingredients, dehydration-sensitive active pharmaceutical ingredients,poorly-compressible active pharmaceutical ingredients, and high-dosageactive pharmaceutical ingredients. In some embodiments, the at least onecarrier is selected from the group consisting of polysaccharides,povidones, acrylates, celluloses and polyols. In some embodiments, theat least one carrier is selected from the group consisting ofhomopolymers and copolymers of N-vinyl pyrrolidone, copolymers ofN-vinyl pyrrolidone and vinyl acetate or vinyl propionate; celluloseesters and cellulose ethers, hydroxyalkylcelluloses,hydroxyalkylalkylcelluloses, cellulose phthalates, cellulose succinates;polyethylene oxide, polypropylene oxide, copolymers of ethylene oxideand propylene oxide; polyacrylates, polymethacrylates, polyacrylamides;vinyl acetate polymers, polyvinyl alcohol, oligo- and polysaccharidesand mixtures of one or more thereof. In some embodiments, the at leastone carrier is selected from the group consisting ofhydroxylpropylcellulose, ethylcellulose, carboxymethylcellulose,hydroxyethylcellulose, methylcellulose, ethylhydroxyethylcellulose,hydroxyethylmethylcellulose, hydrophobically modifiedhydroxyethylcellulose, hydrophobically modifiedethylhydroxyethylcellulose, carboxymethylhydroxyethylcellulose, andcarboxymethyl hydrophobically modified hydroxyethylcellulose. In someembodiments, the at least one carrier is a polymeric carrier having amolecular weight in a range of 2,000-2,000,000 Daltons.

In some embodiments, the granules have an angle of repose of less thanor equal to 30. In some embodiments, the granules have a compressibilityindex of 10-30. In some embodiments, the granules have a Hausner ratioof less than 1.25. In some embodiments, the granules have a true densityof 1.15-1.35. In some embodiments, the granules have a surface area of0.05-0.45. In some embodiments, an oral dosage formulation includes atleast one granule, wherein the oral dosage formulation is a capsule,pellet, sachet, powder, or tablet.

In one aspect, the present invention provides a dry granulation processusing a twin-screw extruder for granulating a powder mixture whichincludes at least one active ingredient and a carrier. The drygranulation process includes the steps of kneading the powder mixture inthe screw barrel of the twin-screw extruder under conditions thatmaintain the barrel temperature below the melting point of the at leastone active ingredient as well as below the melting point or the glasstransition temperature of all of the components contained in the powdermixture to provide a kneaded powder mixture, and extruding the kneadedpowder mixture to form granules.

In another aspect, the screw barrel has plurality of zones spaced alongthe length of the screw barrel and at least one of the zones has abarrel temperature that is different from the barrel temperature of oneor more other zones.

In yet another aspect, a powder lubricant is added to the powder mixtureprior to the kneading step. In one embodiment, the powder lubricant maybe selected from magnesium stearate, zinc stearate, lithium stearate,calcium stearate, aluminum stearate, sodium stearyl fumarate, talc,glyceryl behenate and colloidal silicon dioxide.

In yet another aspect, the least one active ingredient is selected fromheat-sensitive ingredients, dehydration-sensitive ingredients,poorly-compressible ingredients, high-dosage ingredients and ingredientsthat require high-drug loading.

In yet another aspect, the powder mixture includes one or moreadditional components selected from plasticizers, non-polymericcarriers, binders, fillers and disintegrants.

In yet another aspect, granules are provided using the dry granulationprocess of the invention in the twin-screw extruder. Also provided aretablets made from the granules produced by the granulation process ofthe invention.

Reference to “about” a value or parameter herein includes (anddescribes) variations that are directed to that value or parameter perse. For example, description referring to “about X” includes descriptionof “X”. As used herein, the singular forms “a,” “an,” and “the” areintended to include the plural forms as well, unless the context clearlyindicates otherwise. It is also to be understood that the term “and/or”as used herein refers to and encompasses any and all possiblecombinations of one or more of the associated listed items. It isfurther to be understood that the terms “includes,” “including,”“comprises,” and/or “comprising,” when used herein, specify the presenceof stated features, integers, steps, operations, elements, components,and/or units but do not preclude the presence or addition of one or moreother features, integers, steps, operations, elements, components,units, and/or groups thereof.

Additional advantages will be readily apparent to those skilled in theart from the following detailed description. The examples anddescriptions herein are to be regarded as illustrative in nature and notrestrictive.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a flow chart illustrating a dry granulation process accordingto one embodiment of the present disclosure.

FIGS. 2A-2E illustrate various screw designs that may be used in thetwin-screw extruder used to carry out the dry granulation process of thepresent disclosure.

FIGS. 3A-3B are photos showing differences between a molten powder masson the mixing elements of twin screws (FIG. 3A) and a compacted powdermass formed during the twin-screw dry granulation process of thedisclosure (FIG. 3B).

FIG. 4 illustrates a mid-infrared spectrum of the granules produced inExample 1.

FIG. 5 illustrates various screw configurations that were used in thetwin-screw extruder to carry out the dry granulation methods of Example2.

FIG. 6 is a differential scanning calorimetry (DSC) thermogram showingdehydration of ondansetron HCl.2H20 to ondansetron HCl, using the screwconfigurations of FIG. 5 in the methods of Example 2.

FIG. 7 is a DSC thermogram showing dehydration of ondansetron HCl.2H20to ondansetron HCl at various processing conditions.

FIG. 8 is a DSC thermogram showing dehydration of ondansetron HCl.2H20to ondansetron HCl, using a low barrel temperature and the conveyingscrew configuration 1 of FIG. 5 at various screw speeds.

FIG. 9 is a plot showing a thermogravimetric analysis of the ondansetronHCl.2H20 of Example 2.

FIG. 10 is a mass plot of ondansetron HCl.2H20 generated by dynamicvapor sorption, as described in Example 2.

FIG. 11 is a drying curve of ondansetron HCl.2H20 generated by dynamicvapor sorption, as described in Example 2.

FIG. 12 illustrates hot stage microscopy images representing the thermalevents associated with ondansetron HCl.2H20 dehydration.

FIG. 13 illustrates DSC curves of pure ondansetron HCl.2H20 and thepowder mixture of Example 3.

FIG. 14 illustrates digital images of a pre-granulation powder mixtureand granulation products using different screw configurations and atdifferent barrel temperatures, as described in Example 3.

FIG. 15 illustrates contour plots and response surface graphsrepresenting effects on the repose angle of granules of differentgranulation parameters, as described in Example 3.

FIG. 16 illustrates a drug release profile of tablets made from granulesproduced using different granulation parameters, as described in Example3.

FIG. 17 illustrates contour plots and response surface graphsrepresenting effects on the tablet dissolution time of differentgranulation parameters, as described in Example 3.

FIG. 18 illustrates a desirability plot and an overlay plot representinga selected feed rate and screw speed using a Quality by Design approach,as described in Example 3.

FIG. 19 illustrates the total surface energy profile of twin screw drygranulated formulations at various barrel temperatures, as described inExample 2.

DETAILED DESCRIPTION OF THE DISCLOSURE

Although it was known in the art to make granules using twin-screwextruders using a wet granulation process or a melt granulation process,Applicants have developed the use of a twin-screw extruder to makegranules by a dry granulation process. As such, the dry granulationprocess of the present disclosure can be performed without solvent orliquid binders and can facilitate the handling of sensitive ingredientsthat may be subject to dehydration or adversely affected by solvents,excessive heat, or liquid binders. In addition, the present disclosurecan also facilitate the production of high loading granules.

For illustrative purposes, the principles of the present disclosure aredescribed by referencing various exemplary embodiments. Although certainembodiments of the disclosure are specifically described herein, one ofordinary skill in the art will readily recognize that the sameprinciples are equally applicable to, and can be employed in, othersystems and methods. Before explaining the disclosed embodiments of thepresent disclosure in detail, it is to be understood that the disclosureis not limited in its application to the details of any particularembodiment shown. Additionally, the terminology used herein is for thepurpose of description and not for limitation. Furthermore, althoughcertain methods are described with reference to steps that are presentedherein in a certain order, in many instances, these steps can beperformed in any order as may be appreciated by one skilled in the art;the method is therefore not limited to the particular arrangement ofsteps disclosed herein.

As used herein, the term “pharmaceutically acceptable” refers to thosecompounds, materials, and/or compositions which are, within the scope ofsound medical judgment, suitable for contact with the tissues ofmammals, especially humans, without excessive toxicity, irritation,allergic response and other problematic complications commensurate witha reasonable benefit/risk ratio.

As used herein, the term “active pharmaceutical ingredient” or API meansany compound, substance, drug, medicament, or active ingredient having atherapeutic or pharmacological effect, and which is suitable foradministration to a mammal, e.g., a human, in a composition that isparticularly suitable for oral administration.

As used herein, the term “poorly compressible” refers to a compound,composition or granule that does not easily bond to form a tablet uponthe application of a force. A tablet that is poorly compressible wouldhave a weight loss of greater than about 1 weight % when tested forfriability as described in the U.S. Pharmacopeias/National Formulary(USP 23/NF 18, pp 1981). Poorly compressible compounds, compositions orgranules may require additional processing and special formulationmethods, for example wet granulation or roller compacting. High levelsof some active ingredients in the granules may also render thecomposition unsuitable for direct compression because of one or both ofthe poor flowability and poor compressibility of such granules.

As used herein, the term “extended release” refers to the gradual butcontinuous release of the active ingredient content from a solidformulation over a relatively extended period. The release may continuethrough until and after the dosage formulation reaches the intestine.

As used herein, “delayed release” refers to the release of an activeingredient which does not start immediately when the formulation reachesthe stomach but is delayed for a period of time, for instance, untilwhen the dosage formulation reaches the intestine such that theincreasing pH can be used to trigger release of the active ingredientfrom the formulation.

In one aspect, the present disclosure provides a dry granulation processfor making a granular formulation using a twin-screw extruder. In someembodiments, two or more twin-screw extruders may be employed in thesame manner as the twin-screw extruder described herein. In oneembodiment, the dry granulation process may include one or more of thesteps of mixing a powder of at least one active ingredient and a powderof at least one carrier to produce a powder mixture, feeding the powdermixture to a twin-screw extruder having a screw barrel that is heated toa barrel temperature below the melting point of the at least one activeingredient and the melting point or the glass transition temperature ofall of the components of the powder mixture including the carrier,kneading the powder mixture in the screw barrel to form a kneaded powdermixture and extruding the kneaded powder mixture to form granules.

Several granulation parameters may be important for dry granulation of aparticular powder mixture. These parameters can include the screw designused in the twin-screw extruder, feed rate of the powder mixture to thescrew barrel of the twin-screw extruder, the residence time of thepowder mixture in the screw barrel of the twin-screw extruder, and thebarrel temperature and/or temperature profile of the screw barrel of thetwin-screw extruder. These parameters function can be employed to ensurethat the powder mixture is subjected to the conditions required for thepowder to agglomerate and form granules.

One goal of the dry granulation process may be to ensure substantiallyconsistent heating of the powder mixture in the screw barrel of thetwin-screw extruder to avoid localized melting of the active ingredientand/or carrier. Another goal of the dry granulation process may be tosubject the powder mixture to sufficient mechanical shear exerted by therotating screws of the twin-screw extruder to cause agglomeration of thepowder into granules without melting one or more components of thepowder mixture.

In one aspect, the present disclosure provides a Quality by Designapproach in determining the granulation parameters for extrudinggranules made from a particular powder mixture of an active ingredientand a carrier. The Quality by Design approach may be performed byvarying one or more of the granulation parameters and/or the inputcomposition while monitoring the quality of the final product, which maybe the granules and/or tablets made from the granules. The quality ofthe granules may be determined by observing the granules by scanningelectronic microscopy and measuring one or more of the properties of thegranules including, for example, the bulk density, the hardness, thefriability, and weight variation. Similar properties of tablets madefrom the granules may also be measured. In addition, in someembodiments, the crystal structure of the active ingredient ispreferably preserved in the granules as well as in tablets madetherefrom. The crystal structure of the active ingredient may bedetermined by Fourier Transform Infrared Spectroscopy. The Quality byDesign approach is further illustrated by the Examples of the presentapplication.

The twin-screw extruder used in the dry granulation process employs twoscrews located in a single screw barrel for kneading and extruding thepowder mixture. Typically, the screw barrel is provided with a feeder atan inlet and an outlet, preferably with a die block. In a typicalprocess as depicted in FIG. 1 , a powder mixture can be formed in mixingstep 10 and fed 20 to the screw barrel by the feeder. Granules can beproduced by a combination of kneading 30 the powder mixture in the screwbarrel and extruding 40 the powder mixture through a die located at theoutlet. Rotation of the twin screws can propel the powder mixture in thescrew barrel from the inlet to the outlet, as well as kneading 30 thepowder mixture. Examples of twin-screw extruders include, for example,in U.S. Pat. Nos. 4,890,996 and 3,730,663, as well as in Aulton,Pharmaceutics, the Science of Dosage Form Design, (1988) 623-625, thedisclosures of which are hereby incorporated herein by reference intheir entirety.

The dry granulation process may be conducted as a continuoussolvent-free process, in which the powder mixture is continuouslyintroduced into the screw barrel and the granules are continuouslyextruded 40, optionally through a die block from the outlet of the screwbarrel. In some embodiments, the twin-screw extruder may be used in theprocess without the die block in order to prevent over-densification ofmaterial inside the screw barrel.

Two features of the twin-screw extruder used in the present disclosurethat may influence the results of the granulation process are themeshing characteristics and type of rotation of the twin screws. Thetwin screws of the twin-screw extruder may be fully intermeshing,partially intermeshing, or non-intermeshing. The twin screws of thetwin-screw extruder may rotate in opposite directions (counter-rotation)to form a single stream of powder mixture that travels between thescrews. The twin screws may alternatively rotate in the same direction(co-rotation) which forms two streams of powder mixture that travel inparallel along two screws. In one embodiment, the twin-screw extruderemploys co-rotating twin-screws that are fully intermeshing.

The granulation process can be operated under the condition that thescrew barrel of the twin-screw extruder has a barrel temperature that isbelow the melting point of the active ingredient and the melting pointor glass transition temperature of all of the components of the powdermixture including the carrier. In some embodiments, the barreltemperature of the screw barrel is substantially uniform along thelength of the screw barrel. In some other embodiments, the barreltemperature of the screw barrel may vary along the length of the screwbarrel. In such embodiments, there may be a plurality of zones along thelength of the screw barrel, each with a barrel temperature that may bedifferent from the barrel temperature of one or more other zones. Invarious embodiments, there may be from 5 to 12 zones or from 7 to 10zones in the screw barrel (see Table 1 for example). The barreltemperatures of all of the zones can be below the melting point of theactive ingredient and the melting point or the glass transitiontemperature of all of the components of the powder mixture including thecarrier.

In one embodiment, a zone adjacent to the inlet (feed zone) and a zoneat a central portion of the screw barrel between the inlet and outleteach have a barrel temperature higher than the barrel temperature of azone adjacent to the outlet of the screw barrel (outlet zone or diezone). In another embodiment, the zone at the central portion of thescrew barrel has a barrel temperature that is higher than the barreltemperatures of the zones adjacent to the inlet and outlet of the screwbarrel. In yet another embodiment, the barrel temperatures of the zonesadjacent to the inlet and outlet of the screw barrel are substantiallythe same, and are lower than the barrel temperature at the zone at thecentral portion of the screw barrel. Some exemplary configurations ofthe barrel temperatures of the screw barrel are represented in Table 1below.

TABLE 1 Barrel temperatures in the Screw Barrel of the Twin-ScrewExtruder Barrel Temperature (° C.) Feed Zone Zone Zone Zone 2 3 4 Zone 5Zone 6 Zone 7 Zone 8 Die N/A High High High High High Low Low Low N/ALow Low High High High Low Low Low

In some embodiments, each barrel temperature of the screw barrel isbelow the melting point of the active pharmaceutical ingredient and themelting point or glass transition temperature of the polymeric carrierby about 15° C., or about 20° C., or about 25° C., or about 30° C., orabout 35° C., or about 40° C., or about 45° C. Each barrel temperatureof the screw barrel is generally in the range of from about 50° C. toabout 100° C., or from about 50° C. to about 95° C., or from about 55°C. to about 95° C., or from about 55° C. to about 90° C., or from about60° C. to about 90° C., or from about 60° C. to about 85° C., or fromabout 65° C. to about 85° C., or from about 65° C. to about 80° C., orfrom about 70° C. to about 80° C.

In some embodiments, screw barrel is heated to the one or more barreltemperatures in order to transfer heat to the powder mixture therein. Insome embodiments, one or more components of the mixture may be preheatedbefore being fed 20 to the inlet of the twin-screw barrel but careshould be taken to avoid agglomeration if preheating. The powder mixturemay be preheated to a temperature of about 20° C., or about 15° C., orabout 10° C. below a barrel temperature of the screw barrel.

The twin screws of the extruder can knead 30 the powder mixture andpreferably ensure substantially even heating of the powder mixture bythe screw barrel by moving the powder mixture in a certain manner. Thetwin screws can also be employed to impart shearing mechanical energy tothe powder mixture. In the dry granulation process, the thermal energytransferred to the powder mixture from the barrel and the shearingmechanical energy imparted to the powder mixture by the rotating twinscrews can combine to cause granulation of the powder mixture. The screwdesign may be varied to control the dry granulation process becausevariation of the number of mixing elements within a defined length ofthe screw can be used to vary the amount of shearing mechanical energyapplied to the powder mixture.

The twin screws also can function to move the powder mixture from theinlet of the screw barrel to the outlet of the screw barrel at a speedthat determines the residence time of the powder mixture in the screwbarrel. The feed rate of the powder mixture to the screw barrel can alsobe a factor that contributes to determination of the residence time ofthe powder mixture in the screw barrel. Sufficient residence time in thescrew barrel can allow the powder mixture to absorb sufficient heat andto be exposed to sufficient shear energy to ensure agglomeration of thepowder mixture into granules having sufficient hardness and friabilityto provide useful products.

Various screw designs used in twin-screw extruders are shown in FIGS.2A-2E. More specifically, FIG. 2A shows a screw design that is similarto those used in polymer processing or hot melt extrusion operations.Such a screw design can employ numerous mixing elements to impartconsiderable shear energy to the powder mixture within the barrel duringthe kneading step 30. The screw design of FIG. 2B consists of conveyingelements but no mixing elements, and thus can serve to pump the powdermixture through the screw barrel without imparting significant shearenergy thereto. The screw design shown in FIG. 2C is similar to thescrew design of FIG. 2B, except that three mixing elements are addedproximate to the discharge section of the screws that is positioned atthe outlet of the screw barrel. The design of FIG. 2C is capable ofyielding granules, indicating that this screw design can impart asufficient amount of shear energy to the powder mixture for granulationto occur when employed in combination with a heated barrel. Twoadditional screw designs capable of producing granules are shown inFIGS. 2D-2E. In FIG. 2D, the screw is similar to the screw of FIG. 2Cexcept that it has an additional mixing element near the feed zone. Thescrew design in FIG. 2E is a modified version of the screw design ofFIG. 2D wherein the offset angle of the mixing elements proximate to thedischarge section of the screw have been altered.

In certain embodiments, a back pressure in the screw barrel may berequired to facilitate agglomeration of the powder mixture. This backpressure may be achieved by using the twin screws to force the powdermixture in the screw barrel through a die block or an outlet that isnarrower than an adjacent portion of the screw barrel. Such a backpressure is normally not required for agglomeration in hot meltextrusion processes because agglomerated material typically appearsimmediately when the carrier becomes molten. Further, in a meltgranulation process, torque values tend to be steadily elevated up toapproximately 5.3 Nm as the carrier becomes more viscous in the meltmaterial. In contrast, during the dry granulation process of the presentdisclosure, the torque values remain significantly lower with relativelylarge fluctuations ranging from about 0.72-3.12 Nm.

The powder mixture in the screw barrel can undergo agglomeration andforms granules, which may then be extruded 40, optionally through a dieblock, to produce granules. In certain embodiments, the granules may beused to make oral dosage forms such as capsules or tablets.

As will be appreciated by a person skilled in the art, given aparticular powder mixture comprising an active ingredient and ancarrier, the particular granulation parameters for the twin-screw drygranulation process of the disclosure, including at least the screwdesign, feed rate, screw barrel temperature, screw barrel temperatureprofile and residence time may be determined by use of the presentdisclosure in combination with the “Quality by Design” approach with thegoal of obtaining desired granules. It is understood that theseparameter are dependent on each other and also on the composition of thepowder mixture, since different active ingredients and carriers mayrequire different feed rates, barrel temperatures, barrel temperatureprofiles, residence times, and/or screw designs for producing thedesired granules. In some embodiments, one or more characteristics ofthe granules may be used to determine the granulation parameters. Thesecharacteristics include one or more of the preservation of thecrystalline lattice of a crystalline active ingredient, granule surfacemorphology, phase changes of the active ingredient, chemicalinteractions, firmness, friability, the compressibility index, the angleof repose, the Hausner ratio, and any other relevant property of thegranules.

In some embodiments, the angle of repose of the granules can be lessthan about 50, less than about 45, less than about 40, less than about35, or less than or equal to about 30. In some embodiments, the angle ofrepose of the granules can be about 15-50, about 20-45, about 25-40,about 25-35, or about 25-30.

In some embodiments, the (Carr's) compressibility index is less thanabout 30, less than about 25, less than about 20, or less than about 15.In some embodiments, the (Carr's) compressibility index of the granulesis about 1-40, about 4-30, about 10-30, about 15-25, or about 19-21. Insome embodiments, the Hausner ratio of the granules can be less thanabout 1.5, less than about 1.4, less than about 1.3, or less than about1.25. In some embodiments, the Hausner ratio of the granules can beabout 1-1.35, about 1-1.3, about 1-1.25, or about 1-1.2.

In some embodiments, the true density of the granules is about 1.1-1.4,about 1.15-1.35, or about 1.2-1.3. In some embodiments, the surface areaof the granules is about 0.01-0.5, about 0.05-0.45, or about 0.1-0.4. Insome embodiments, the percentage of fines (particles with a size lessthan 500 μm) of the granules produced is less than about 50%, less thanabout 40%, less than about 30%, less than about 20%, less than about15%, less than about 10%, less than about 8%, less than about 7%, lessthan about 6%, less than about 5%, less than about 4%, or less thanabout 3%.

Further, the suitability of the granules for the production of tabletsor other solid formulations with desired properties can also beevaluated and employed for the purpose of determining suitablegranulation parameters. For, example, in the case of tablets or othersolid formulations, properties such as the ability to provide a highloading of active ingredient, storage stability, hardness, friability,and extended or delayed release properties may also be used for thepurpose of determining one or more of the granulation parameters.

In some embodiments, a tablet or other solid formulation produced fromthe granules disclosed herein has a hardness of about 1-20 kp, about5-20 kp, about 8-20 kp, or about 10-20 kp. In some embodiments, a tabletor other solid formulation produced from the granules disclosed hereinhas a friability of about 0-0.5%, about 0-0.4%, about 0-0.3%, about0-0.2%, about 0-0.1%, or about 0-0.05%.

The present disclosure surprisingly found that without having to add asolvent, a liquid binder to the powder mixture, and without having tomelt a component of the powder mixture, the dry granulation process ofthe disclosure when carried out in an appropriate twin-screw extrudercan provide acceptable granules with desired properties. This drygranulation process can greatly simplify the formulation of many activeingredients since this process does not require high temperatures,solvents or liquid binders, and/or subsequent drying operations.

The active ingredients that may be used in the dry granulation processof the present disclosure may include active pharmaceutical ingredients,vitamins, minerals, and nutritional components. In particular, activepharmaceutical ingredients for which the present dry granulation processmay be used include, but are not limited to antacids, anti-inflammatorysubstances, coronary dilators, cerebral dilators, peripheralvasodilators, anti-infectives, psychotropics, antimanics, stimulants,antihistamines, anti-cancer therapeutic compounds, laxatives,decongestants, vitamins, gastrointestinal sedatives, antidiarrhealpreparations, anti-anginal therapeutic compounds, vasodilators,antiarrythmics, anti-hypertensive therapeutic compounds,vasoconstrictors and migraine treatments, anticoagulants andantithrombotic therapeutic compounds, analgesics, antipyretics,hypnotics, sedatives, anti-emetics, anti-nauseants, anti-convulsants,neuromuscular therapeutic compounds, hyper- and hypoglycemic agents,thyroid and antithyroid preparations, diuretics, anti-spasmodics,uterine relaxants, mineral and nutritional additives, anti-obesitytherapeutic compounds, anabolic therapeutic compounds, erythropoietictherapeutic compounds, anti-asthmatics, expectorants, coughsuppressants, mucolytics, anti-uricemic therapeutic compounds, andtherapeutic compounds or substances acting locally in the mouth.

Exemplary active pharmaceutical ingredients that may be used in the drygranulation process of the disclosure include, but are not limited to,gastrointestinal sedatives, such as metoclopramide and propanthelinebromide; antacids, such as aluminum trisilicate, aluminum hydroxide andcimetidine; anti-inflammatory therapeutic compounds, such asphenylbutazone, indomethacin, naproxen, ibuprofen, flurbiprofen,diclofenac, dexamethasone, prednisone and prednisolone; coronaryvasodilator therapeutic compounds, such as glyceryl trinitrate,isosorbide dinitrate and pentaerythritol tetranitrate; peripheral andcerebral vasodilators, such as soloctidilum, vincamine, naftidrofuryloxalate, co-dergocrine mesylate, cyclandelate, papaverine and nicotinicacid; anti-infective therapeutic compounds, such as erythromycinstearate, cephalexin, nalidixic acid, tetracycline hydrochloride,ampicillin, flucolaxacillin sodium, hexamine mandelate and hexaminehippurate; neuroleptic therapeutic compounds, such as fluazepam,diazepam, temazepam, amitryptyline, doxepin, lithium carbonate, lithiumsulfate, chlorpromazine, thioridazine, trifluperazine, fluphenazine,piperothiazine, haloperidol, maprotiline hydrochloride, imipramine anddesmethylimipramine; central nervous stimulants, such asmethylphenidate, ephedrine, epinephrine, isoproterenol, amphetaminesulfate and amphetamine hydrochloride; anti-histamic therapeuticcompounds such as diphenhydramine, diphenylpyraline, chlorpheniramineand brompheniramine; anti-diarrheal therapeutic compounds, such asbisacodyl and magnesium hydroxide; laxative therapeutic compounds, suchas dioctyl sodium sulfosuccinate; nutritional supplements, such asascorbic acid, alpha tocopherol, thiamine and pyridoxine; anti-spasmotictherapeutic compounds, such as dicyclomine and diphenoxylate;therapeutic compounds effecting the rhythm of the heart, such asverapamil, nifedepine, diltiazem, procainamide, disopyramide, bretyliumtosylate, quinidine sulfate and quinidine gluconate; therapeuticcompounds used in the treatment of hypertension, such as propranololhydrochloride, guanethidine monosulphate, methyldopa, oxprenololhydrochloride, captopril and hydralazine; therapeutic compounds used inthe treatment of migraine, such as ergotamine; therapeutic compoundseffecting coagulation of blood, such as epsilon aminocaproic acid andprotamine sulfate; analgesic therapeutic compounds, such asacetylsalicylic acid, acetaminophen, codeine phosphate, codeine sulfate,oxycodone, dihydrocodeine tartrate, oxycodeinone, morphine, heroin,nalbuphine, butorphanol tartrate, pentazocine hydrochloride,cyclazacine, pethidine, buprenorphine, scopolamine and mefenamic acid;anti-epileptic therapeutic compounds, such as phenytoin sodium andsodium valproate; neuromuscular therapeutic compounds, such asdantrolene sodium; therapeutic compounds used in the treatment ofdiabetes, such as metformin, tolbutamide, diabenase glucagon andinsulin; therapeutic compounds used in the treatment of thyroid glanddysfunction, such as triiodothyronine, thyroxine and propylthiouracil;diuretic therapeutic compounds, such as furosemide, chlorthalidone,hydrochlorthiazide, spironolactone and triampterene; uterine relaxanttherapeutic compounds, such as ritodrine; appetite suppressants, such asfenfluramine hydrochloride, phentermine and diethylproprionhydrochloride; anti-asthmatic therapeutic compounds, such asaminophylline, theophylline, salbutamol, orciprenaline sulphate andterbutaline sulphate, expectorant therapeutic compounds, such asguaiphenesin; cough suppressants, such as dextromethorphan andnoscapine; mucolytic therapeutic compounds, such as carbocisteine;anti-septics, such as cetylpyridinium chloride, tyrothricin andchlorhexidine; decongestant therapeutic compounds, such asphenylpropanolamine and pseudoephedrine; hypnotic therapeutic compounds,such as dichloralphenazone and nitrazepam; anti-nauseant therapeuticcompounds, such as promethazine theoclate; haemopoetic therapeuticcompounds, such as ferrous sulphate, folic acid and calcium gluconate,uricosuric therapeutic compounds, such as sulphinpyrazone, allopurinoiand probenecid and the like.

The dry granulation process can be particularly suitable for certaintypes of active ingredients. In particular, the dry granulation processmay provide advantages when applied to active ingredients that arepoorly compressible, sensitive to dehydration or hydrolysis undertypical granulation conditions, active ingredients for which it isdesired to provide a relatively high ratio of active ingredient tocarrier, such as for high dose pharmaceutical actives, as well as activeingredients sensitive to heating or high temperatures that may beencountered, for example, in melt granulation processes. The drygranulation process may also be used to produce extended or delayedrelease formulations.

The dry granulation process of the present disclosure can also beparticularly suitable for active pharmaceutical ingredients that aresensitive to dehydration under heat or otherwise sensitive to heat ingeneral. For these active pharmaceutical ingredients, excessive heatwill decompose the active pharmaceutical ingredients, such asdehydration. As used herein, the term “sensitive to heat” means anactive pharmaceutical compound which undergoes a minimum of 5%degradation at about 40° C. As used herein, the term “sensitive todehydration” means an active pharmaceutical compound which undergoes aminimum of 5% dehydration at about 40° C.

The carrier used in the dry granulation process of the presentdisclosure is typically a polymeric material that has a melting point ora glass transition temperature not exceeding the melting point ormelting range of the active ingredient. Examples of polymers suitablefor use as carriers in the dry granulation process of the disclosureinclude, but are not limited to, homopolymers and copolymers of N-vinyllactams, e.g., homopolymers and copolymers of N-vinyl pyrrolidone (e.g.,polyvinylpyrrolidone), copolymers of N-vinyl pyrrolidone and vinylacetate or vinyl propionate; cellulose esters and cellulose ethers(e.g., methylcellulose and ethylcellulose) hydroxyalkylcelluloses (e.g.,hydroxypropylcellulose), hydroxyalkylalkylcelluloses (e.g.,hydroxypropylmethylcellulose), cellulose phthalates (e.g., celluloseacetate phthalate and hydroxypropylmethylcellulose phthalate) andcellulose succinates (e.g., hydroxypropylmethylcellulose succinate orhydroxypropylmethylcellulose acetate succinate); high molecularpolyalkylene oxides such as polyethylene oxide and polypropylene oxideand copolymers of ethylene oxide and propylene oxide; polyacrylates andpolymethacrylates (e.g., methacrylic acid/ethyl acrylate copolymers,methacrylic acid/methyl methacrylate copolymers, butylmethacrylate/2-dimethylaminoethyl methacrylate copolymers,poly(hydroxyalkyl acrylates), poly(hydroxyalkyl methacrylates));polyacrylamides; vinyl acetate polymers such as copolymers of vinylacetate and crotonic acid, partially hydrolyzed polyvinyl acetate;polyvinyl alcohol; and oligo- and polysaccharides such as carrageenans,galactomannans and xanthan gum, or mixtures of one or more thereof.

Examples of derivatives of hydroxylpropylcellulose or ethylcellulosethat are useful carriers for the present disclosure include anionicmodifications, such as addition of a carboxymethyl moiety, cationicmodifications, such as the provision of hydroxypropyltrimethylammoniumsalts, and nonionic modifications, such as addition of one or more alkylor arylakyl moieties having 2 to 30 carbon atoms.

Examples of polysaccharides useful as carriers in the dry granulationprocess of the present disclosure include carboxymethylcellulose,hydroxyethylcellulose, methylcellulose, ethylhydroxyethylcellulose,hydroxyethylmethylcellulose, hydrophobically modifiedhydroxyethylcellulose, hydrophobically modifiedethylhydroxyethylcellulose, carboxymethylhydroxyethylcellulose,carboxymethyl hydrophobically modified hydroxyethylcellulose, guar andguar derivatives, pectin, carrageenan, xanthan gum, locust bean gum,agar, algin and its derivatives, gellan gum, gum acacia, starch andmodified starches. Examples of synthetic polymers useful as carriers inthe dry granulation process of the present disclosure are mono- andco-polymers of carboxyvinyl monomers, mono- and co-polymers of acrylatesor methacrylates monomers, mono- and co-polymers of oxyethylene, oroxypropylene monomers.

In some embodiments, the powder mixture includes a mixture of two ormore carriers, one or more of which may be, for example, polymericcarriers. Each of the two or more carriers may be selected from the listprovided above.

Suitable molecular weights for polymeric carriers used in thisdisclosure can be determined by a person of ordinary skill in the art,taking into consideration factors such as the desired polymerdegradation rate, physical properties of the polymer such as mechanicalstrength and end group chemistry. Typically, a suitable range ofmolecular weight for the polymeric carrier is of from about 2,000Daltons to about 2,000,000 Daltons, or from about 4,000 Daltons to about1,800,000 Daltons, or from about 8,000 Daltons to about 1,600,000Daltons, or from about 10,000 Daltons to about 1,400,000 Daltons, orfrom about 15,000 Daltons to about 1,200,000 Daltons, or from about20,000 Daltons to about 1,000,000 Daltons, or from about 40,000 Daltonsto about 1,000,000 Daltons.

In some embodiments, the active ingredient and carrier are mixed in aratio in the range of about 99:1 to about 1:1 (on a dry weight basis)prior to, or upon addition into the feeder of the twin-screw extruder.In one exemplary embodiment, this ratio may be in the range of about97:3 to about 60:40 (on a dry weight basis). In another embodiment, theratio can be in a range of about 97:3 to about 75:25 (on a dry weightbasis).

The dry granulation process of the present disclosure is also suitablefor producing extended or delayed release formulations by selecting asuitable carrier. Polymeric carriers suitable for producing the extendedrelease formulation include poly(lactides), poly(glycolides),poly(lactide-co-glycolides), poly(lactic acid)s, poly(glycolic acid)s,polycarbonates, polyesteramides, polyanydrides, poly(amino acids),polyorthoesters, poly(dioxanone)s, poly(alkylene alkylate)s,polyethylene glycol and polyorthoester, biodegradable polyurethane,blends thereof.

There are other components that may be added to the powder mixturebefore dry granulation. These optional components include but are notlimited to plasticizers, binders, fillers, lubricants, glidants,sweeteners, flavorants, colorants, and disintegrants. These componentsare required to be in a solid form at the barrel temperature of thescrew barrel.

As used herein, the term “plasticizer” refers to a material that may beincorporated into the powder mixture in order to decrease the glasstransition temperature and the melt viscosity of a polymer by increasingthe free volume between polymer chains. The plasticizer can be presentin concentration from about 0% to about 15%, e.g., about 0.5% to about5% by weight of the powder mixture. Examples of plasticizers can befound in, for example, The Handbook of Pharmaceutical Excipients, 7thedition, Rowe et al., Eds., American Pharmaceuticals Association (2012);and Remington: the Science and Practice of Pharmacy, 22nd edition,Gennaro, Ed., Lippincott Williams & Wilkins (2012), which is herebyincorporated by reference in its entirety.

Examples of disintegrants include, but are not limited to, starches,clays, celluloses, alginates, gums, cross-linked polymers, e.g.,cross-linked polyvinyl pyrrolidone or crospovidone, cross-linked sodiumcarboxymethylcellulose or croscarmellose sodium, and cross-linkedcalcium carboxymethylcellulose, soy polysaccharides, and guar gum. Thedisintegrant may be present in an amount of from about 0% to about 10%by weight of the powder mixture. In one embodiment, the disintegrant ispresent in an amount from about 0.1% to about 1.5% by weight of thepowder mixture.

Examples of binders include, but are not limited to, starches,celluloses and derivatives thereof, for example, microcrystallinecellulose, hydroxypropyl cellulose hydroxylethyl cellulose andhydroxypropylmethyl cellulose, sucrose, dextrose, and polysaccharides.The binder may be present in an amount from about 0% to about 50%, e.g.,about 10 to about 40% by weight of the powder mixture.

Examples of fillers and diluents include, but are not limited to,confectioner's sugar, compressible sugar, dextrates, dextrin, dextrose,lactose, mannitol, microcrystalline cellulose, powdered cellulose,sorbitol, sucrose and talc. The filler and/or diluent may be present inan amount of from about 0% to about 40% by weight, preferably about 15%to about 40% by weight of the powder mixture.

In some embodiments, the powder mixture may additionally contain a pHadjusting agent such as an acid or base mixed with the other powdersprior to granulation. Suitable organic acids include citric acid, malicacid, maleic acid adipic acid, fumaric acid and the like. Suitable basesinclude calcium carbonate, sodium bicarbonate, calcium phosphatetribasic, dibasic sodium phosphate, sodium carbonate and the like.

The granules produced from such a powder mixture may be suitable forproducing an extended release formulation.

In some embodiments, a powder lubricant may be added to the powdermixture for lubricating the screw barrel and rotating screws, thuspreventing metal on metal contact during the dry granulation process.This powder lubricant can be selected to be a solid at the barreltemperature of screw barrel. Examples of powder lubricants includemagnesium stearate, zinc stearate, lithium stearate, calcium stearate,aluminum stearate, sodium stearyl fumarate, talc, glyceryl behenate andcolloidal silicon dioxide. Other suitable powder lubricants may includecolloidal silica, magnesium trisilicate, starches, tribasic calciumphosphate, magnesium carbonate, magnesium oxide, polyethylene glycol,powdered cellulose and microcrystalline cellulose.

In one embodiment, the powder lubricant is added in an amount of fromabout 0.01 to about 1 wt. % of the powder mixture, or from about 0.05 toabout 0.75 wt. % of the powder mixture, or from about 0.1 to about 0.5wt. % of the powder mixture, or from about 0.15 to about 0.3 wt. % ofthe powder mixture, or from about 0.15 to about 0.25 wt. % of the powdermixture. In some embodiments, the powder lubricant is preferably addedto the powder mixture during the final stage of geometric dilution ofthe powder mixture because it was found that, in some embodiments,earlier addition of the lubricant may prevent forming of granules withdesired hardness.

As used herein, the term “geometric dilution” is a pharmaceutical termreferring to the extemporaneous method of efficiently combining twounequal amounts of a powdered substance to form a homogenous mixture.The concept of geometric dilution centers on the successive addition andblending of equal quantities of materials.

In some embodiments where little or no powder lubricant is added to thepowder mixture, the rotation speed for the screws of the twin-screwextruder may be less than about 200 rpm, or less about 180 rpm, or lessthan about 160 rpm, or less than about 140 rpm, or less than about 130rpm, or less than about 120 rpm, or less than about 110 rpm, or lessthan about 100 rpm, or less than about 90 rpm, or less than about 80rpm, or less than about 70 rpm, or less than about 60 rpm. In someembodiments, the rotation speed for the screws of the twin-screwextruder can be between about 10-200 rpm, about 25-150 rpm, about 25-100rpm, or about 25-50 rpm.

In some embodiments, the feed rate into the twin-screw extruder is lessthan about 500 g/hr, less than about 400 g/hr, less than about 300 g/hr,less than about 250 g/hr, less than about 200 g/hr, less than about 150g/hr, less than about 100 g/hr, or less than about 50 g/hr. In someembodiments, the feed rate into the twin-screw extruder is about 10-500g/hr, about 25-300 g/hr, about 38-300 g/hr, about 80-300 g/hr, about80-240 g/hr, about 80-180 g/hr, or about 100-180 g/hr. In someembodiments, the feed rate can be higher than 500 g/hr.

The twin-screw extruder typically extrudes granules that are infiber-like shape. The fiber-like granules are often chopped or milledinto particles that may later be filled into capsules or sachets, orcompressed into tablets. In some embodiments, the twin-screw extrudermay additionally comprise a chopping device for chopping the fiber-likegranules into particles. The chopping device can be preferably placedproximate to the die block such that the granules discharged from thedie block are immediately chopped into particles.

In some other embodiments, the granules may be collected from thetwin-screw extruder and cooled. The cooled granules can be milled toproduce particles of desired sizes. Once the cooled granules or milledparticles are obtained, they may be formulated into formulations, suchas tablets, pills, lozenges, caplets, capsules or sachets. Theseformulations may include additional conventional carriers as an externalphase of the pharmaceutical composition. These carriers are located onthe outside of the granules and thus are referred to as extragranularcarriers, to be distinguished from the intragranular carrier(s) that arepresent during the dry granulation process.

Examples of such extragranular carriers include, but are not limited to,release retardants, plasticizers, disintegrants, fillers, binders,lubricants, glidants, stabilizers, fillers and diluents. Theplasticizers, non-polymeric carriers, binders, fillers and disintegrantshave been discussed above. The amount of each extragranular carrier usedmay vary within ranges conventional in the art. The following referenceswhich are all hereby incorporated by reference herein disclosetechniques and carriers used to formulate oral dosage formulations. SeeThe Handbook of Pharmaceutical Excipients, 7th edition, Rowe et al.,Eds., American Pharmaceuticals Association (2012); and Remington: theScience and Practice of Pharmacy, 22nd edition, Gennaro, Ed., LippincottWilliams & Wilkins (2012).

Once the granules are compressed into tablets, they can be optionallycoated with a functional or nonfunctional coating as known in the art.Examples of coating techniques include, but are not limited to, sugarcoating, film coating, microencapsulation and compression coating. Typesof coatings include, but are not limited to, extended or delayed releasecoatings.

The disclosure also comprises granules produced by the dry granulationprocess of the disclosure, as well as tablets and capsules made fromsuch granules including oral dosage forms containing an activepharmaceutical ingredient and high dosage oral formulations containingan active pharmaceutical ingredient.

In some embodiments, the time to 80% dissolution of the tablet or othersolid formulation produced from the granules disclosed herein is about1-20 hours, about 3-20 hours, about 5-15 hours, or about 12-14 hours. Insome embodiments, the time to 100% dissolution or 100% drug release isabout 1-20 hours, about 5-20 hours, about 6-18 hours, about 10-18 hours,or about 12-16 hours.

It must be noted that as used herein and in the appended claims, thesingular forms “a”, “an”, and “the” include plural references unless thecontext clearly dictates otherwise. Furthermore, the terms “a” (or“an”), “one or more”, and “at least one” can be used interchangeablyherein. The terms “comprising”, “including”, “having” and “constructedfrom” can also be used interchangeably.

Unless otherwise indicated, all numbers expressing quantities ofingredients, properties such as molecular weight, percent, ratio,reaction conditions, and so forth used in the specification and claimsare to be understood as being modified in all instances by the term“about,” whether or not the term “about” is present. Accordingly, unlessindicated to the contrary, the numerical parameters set forth in thespecification and claims are approximations that may vary depending uponthe desired properties sought to be obtained by the present disclosureand the normal expected variation in the art. At the very least, and notas an attempt to limit the application of the doctrine of equivalents tothe scope of the claims, each numerical parameter should at least beconstrued in light of the number of reported significant digits and byapplying ordinary rounding techniques. Notwithstanding that thenumerical ranges and parameters setting forth the broad scope of thedisclosure are approximations, the numerical values set forth in thespecific examples are reported as precisely as possible. Any numericalvalue, however, inherently contains certain errors necessarily resultingfrom the standard deviation found in their respective testingmeasurements.

It is to be understood that each component, compound, substituent, orparameter disclosed herein is to be interpreted as being disclosed foruse alone or in combination with one or more of each and every othercomponent, compound, substituent, or parameter disclosed herein.

It is also to be understood that each amount/value or range ofamounts/values for each component, compound, substituent, or parameterdisclosed herein is to be interpreted as also being disclosed incombination with each amount/value or range of amounts/values disclosedfor any other component(s), compounds(s), substituent(s), orparameter(s) disclosed herein and that any combination of amounts/valuesor ranges of amounts/values for two or more component(s), compounds(s),substituent(s), or parameters disclosed herein are thus also disclosedin combination with each other for the purposes of this description.

It is further understood that each lower limit of each range disclosedherein is to be interpreted as disclosed in combination with each upperlimit of each range disclosed herein for the same component, compounds,substituent, or parameter. Thus, a disclosure of two ranges is to beinterpreted as a disclosure of four ranges derived by combining eachlower limit of each range with each upper limit of each range. Adisclosure of three ranges is to be interpreted as a disclosure of nineranges derived by combining each lower limit of each range with eachupper limit of each range, etc. Furthermore, specific amounts/values ofa component, compound, substituent, or parameter disclosed in thedescription or an example is to be interpreted as a disclosure of eithera lower or an upper limit of a range and thus can be combined with anyother lower or upper limit of a range or specific amount/value for thesame component, compound, substituent, or parameter disclosed elsewherein the application to form a range for that component, compound,substituent, or parameter.

The following examples are illustrative, but not limiting, of the softgelatin capsules of the present disclosure. Other suitable modificationsand adaptations of the variety of conditions and parameters normallyencountered in the field, and which are obvious to those skilled in theart, are within the scope of the disclosure.

EXAMPLES Example 1: Dry Granulation of Sildenafil Citrate

Sildenafil citrate was formulated into a high drug dose, extendedrelease tablet formulation using the twin-screw dry granulation processof the present disclosure. Specifically, the granules' surfacemorphology, sildenafil citrate crystalline structure, high drug dose,sildenafil citrate phase changes, chemical interactions, andconventional granule properties including compressibility index, angleof repose, and Hausner ratio, were used as quality requirements.

The methods used in this example for assessing the product qualityincluded evaluating drug uniformity in tablets in accordance with UnitedStates Pharmacopeia (USP) specification ranges, assessment ofconventional granule and uncoated tablet properties (as outlined in theUSP), differential scanning calorimetry (DSC), thermogravimetricanalysis (TGA), hot stage microscopy (HSM), mid-infrared (MIR)spectroscopy, and scanning electron microscopy (SEM).

The materials used in this example included hydroxyethyl cellulose (HEC,Natrasol™ 250 L), ethyl cellulose (EC, Aqualon™ N7), hydroxypropylcellulose (HPC, Klucel™ HF) and sildenafil citrate, obtained fromAshland Specialty Ingredients (Wilmington, Del.). Magnesium stearate,hydrochloric acid and the solvents used in this example (analyticalgrade methanol) were purchased from Fisher Scientific (Norcross, Ga.).

Prior to drug granulation, the polymers (hydroxyethyl cellulose, ethylcellulose, hydroxypropyl cellulose) were sieved using a USP #35 meshscreen to remove any aggregates that may have formed. The components(sildenafil citrate and polymers) used in each powder mixture weregeometrically diluted using a glass mortar and pestle.

Various screw designs with different configurations were used in thisexample, as shown in FIGS. 2A-2E. FIG. 2A shows a screw design that wassimilar to those used in polymer processing or hot-melt extrusionoperations, which had numerous mixing elements capable of impartingconsiderable shear to the powder mixture. This configurationconsistently resulted in melting the powder mixture at any appreciablescrew speed. The screw design shown in FIG. 2B consisted of allconveying elements but no mixing elements. This configuration merelypumped the powder mixture through the extruder's screw barrel withoutgranulation of the powder mixture.

The screw design shown in FIG. 2C had three mixing elements added nearthe discharge end of the screw design shown in FIG. 2B. The screw designof FIG. 2C was capable of producing granules. Two additional screwdesigns shown in FIGS. 2D-2E were shown to be capable of producinggranules. In FIG. 2D, the screw design had an additional mixing element,relative to the design of FIG. 2C, added closer to the feeding zone. Thescrew design in FIG. 2E was a modified version of the screw design inFIG. 2D where the mixing elements near the discharge section of thescrew were altered to change the offset angle.

FIGS. 3A-3B provide a visual comparison of the powder mixture in themixing zones of a screw barrel used in hot melt extrusion process and adry granulation process, respectively. The dry powder mixture of FIG. 3Bwas being conveyed and kneaded in the mixing zone of the screw barrel ina dry granulation process. The matte appearance of the powder mixture inthe mixing zone indicates that the mass on the mixing elements was in adry compacted form. Additionally, the ability to easily crush thecompacted mass back into a fine powder further indicated that dryagglomerates were being formed. In contrast, the material in the mixingzone in a hot melt extrusion as shown in FIG. 3A had a glossy appearancethat commonly results from complete melting of polymers. The melted masscould not be easily removed, nor crushed back into its original finepowder form.

In order to prevent product degradation and/or contamination as well asdamage to the twin-screw extruder, a solid lubricant (magnesiumstearate) was added to the powder mixture of sildenafil citrate andpolymeric intragranular carrier. The same lubricant was also used as anextragranular carrier to reduce noise during a later tableting processstep.

While the addition of modest amounts of magnesium stearate (0.2%)eliminated the grinding noises from the extruder, it was observed thatrelatively larger quantities (0.5%) resulted in unacceptably highportion of fine powders exiting the screw barrel. The addition of evenlarger quantities of magnesium stearate (1.0%) frequently prevented theformation of granules entirely. The addition of magnesium stearate intothe powder mixture needed to occur during the final stage of geometricdilution of the drug as earlier addition would also prevent granuleformation. Finally, when the quantity of lubricant was not sufficient toeliminate the noise from the extruder, the screw speed was limited to amaximum of 200 rpm. The percent of intergranular magnesium stearateadded to the powder mixture for lubricating the screws was fixed at0.2%, while extragranular magnesium stearate used to lubricate thetablet machine was fixed at 0.5%.

A buildup of back pressure was required to facilitate the agglomerationof some compositions.

All of the tested polymers (ethyl cellulose (EC), hydroxypropylcellulose (HPC) & hydroxyethyl cellulose (HEC)) were found capable ofproducing granules using the dry granulation process of the presentdisclosure, though this example used polymeric carriers that were blendsof HPC and HEC.

A fully intermeshing, co-rotating, twin-screw extruder (11 mm Process11™, ThermoFisher Scientific) was used to dry granulate a powder mixtureof sildenafil citrate and polymers (HPC and HEC blends). After allowingthe extruder to reach steady state, the produced granules were collectedfrom the extruder and stored in polyethylene bags for further processingand/or analysis.

Steady state processing was observed to have occurred when each zone ofthe extruder barrel, excluding the hopper, maintained a temperature of65° C. (constant for all experiments), and the feed rate of 3-5 g/min.and screw speed (100, 150 or 200 rpm) were maintained for a durationexceeding the residence time of the in-process material.

The granules were used to produce tablets using a single station tabletpress (Globe) with an 8.0 mm flat face tooling. The compression forcewas set to 100, 200, or 300 kg/cm2. Compression forces greater than 300kg/cm2 resulted in formulation leakage around the compression tooling.The addition of 0.2% magnesium stearate as an extragranular carrierprevented adherence of granulated particles or the complete dosage formto the tooling (picking and sticking).

A dual scooping projection Vanderkamp friabilator (Vankel IndustriesInc. Chatham, N.J.) was used to assess tablet friability. Thefriabilator was filled with 33 tablets (at 200 mg each) in one side andallowed to rotate continuously for four minutes at 25 rpm. The tabletswere accurately weighed prior to the test, and carefully de-dusted andreweighed after the test. The weight reduction was indicative of thetablet friability.

Tablet hardness was assessed using a Schleuniger hardness tester. Eachtablet was placed firmly against the stationary anvil prior to beginningthe test, and all debris from the previous test was carefully removedbefore performing replicate tests (n=10). Weight variations in thetablets were measured on a microbalance. Twenty tablets were weighed,and their average determined. The weight of the individual tablets wasthen compared to the average and evaluated within USP specifiedtolerances for uncoated tablets (±7.5%).

The tablets were assessed for in vitro drug release in 900 ml gastricmedia (0.01N HCl) using USP apparatus I (Hanson SR8) at 37±0.5° C. witha basket rotation speed of 100 rpm over a 24 hour period. Thedissolution vessels were equipped with UV-Vis fiber optic probes(Rainbow Dissolution Monitor, pION) and the detector was set at awavelength of 290 nm.

The hardness and friability of the tablets in 16 runs are presented inTable 2.

TABLE 2 Tablet Friability and Hardness Run Friability (%) Hardness (kp)1 0.04970179 15.76667 2 0.18181818 15.96667 3 0.09955202 15.86667 40.09861933 18.73333 5 0 11.53333 6 0.04945598 12.6 7 0.15052684 14.033338 0.29865605 8.566667 9 0.0990099 13.63333 10 0.05005005 11.2 11 0 12.112 0 11.76667 13 0 15.03333 14 0.05037783 17.3 15 0.04985045 13.4 160.15052684 14.4

The fractional factorial model with two center points was utilized todetermine which granulation parameters caused the most significanteffects. The final product quality and the ranges of the parameters, aswell as the main factors that provided a statistically significantcontribution to the responses are listed in Table 3.

TABLE 3 TABLE 3. Statistically Significant Main Factors Response RangeMain Effect (s) Percent Fines   12-49% Screw Configuration, PolymerRatio & Drug Loading Angle of Repose 22.02-38.66 Polymer RatioCompressibility Index  4.76-28.17 Screw Configuration Hausner Ratio1.05-1.39 Screw Configuration API Crystallinity Always Maintained N/ATablet Hardness  8.6-18.7 Screw Configuration, Compression Force & DrugLoading Tablet Friability   0-0.3 Drug Loading & Screw Speed Time to 80%Dissolution   3-15.5 Polymer Ratio & Drug Loading

After the fractional factorial model, a full factorial (2³) model withfour center points (Table 4) was used to evaluate interactions betweenthe main factors, and to numerically determine best values for the mainfactors (granulation parameters). The extruder's volumetric feederoutput was set to 4 g/min and the screw speed was maintained at 150 rpm.The barrel temperature was held at 65° C. from zone 2 to the barrel exit(granule discharge, see also Table 1). The statistically significantmain factors (granulation parameters) and their interactions are listedin Table 5.

TABLE 4 2³ Full Factorial with 4 Center Points Screw Polymer Ratio DrugFines Hausner 80% Disso. Run Design (HPC:HEC) Loading (%) (%) IndexCompressibility (hr.)  1 1 3:1 50 13.2 1.32 24 12.5  2 2 1.7:1 42.5 14.01.34 25 11.5  3 2 3:1 35 10.5 1.29 22 15  4 2 1:1 35 13.5 1.16 14 11.5 5 1 1.7:1 42.5 13.1 1.26 21 14  6 1 1.7:1 42.5 10.3 1.32 24 12  7 1 1:150 17.1 1.30 23  8.5  8 2 1.7:1 42.5 13.2 1.32 24 12  9 2 1:1 50 10.71.25 20  6.5 10 1 3:1 35 10.7 1.19 16 15 11 2 3:1 50 12.6 1.24 19 11 121 1:1 35 11.0 1.29 23  8

TABLE 5 Response Ranges and Statistically Significant Main FactorsResponse Range Main Factors and Interactions Percent Fines 10.32-17.08%Screw Configuration, Polymer Ratio & Drug Loading (3 way interaction)Compressibility Index 13.51-25.37   Screw Configuration, Polymer Ratio &Drug Loading (3 way interaction) Hausner Ratio 1.16-1.34   ScrewConfiguration, Polymer Ratio & Drug Loading (3 way interaction) Time to80% Dissolution 6.5-15    Polymer Ratio & Drug Loading (Main Effects)

The potentially suitable dry granulation settings are given in Table 6.

The screw design 1 in Table 6 was the screw configuration of FIG. 2D andthe screw design 2 in Table 6 was the screw configuration of FIG. 2E.Setting number 1 was selected as it incorporated the highest drugloading and it possessed the highest desirability. The predicted valuesof setting number 1 and predicted product properties were then comparedto the measured values (Table 7).

TABLE 6 Predicted Dry Granulation Settings Screw Polymer Drug HausnerTime to 80% Number Configuration Ratio Load Index CompressibilityDissolution Desirability 1 1 0.75 42.69 1.25 19.7 13.82 0.558 2 1 0.7541.56 1.24 19.36 13.9 0.526 3 2 0.61 36.90 1.25 20.98 12.9 0.196 4 20.61 36.68 1.25 21.03 13.0 0.194

TABLE 7 Measured Values of #1 Setting No. 1 Screw Polymer Drug HausnerTime to 80% Number Configuration Ratio Load Index CompressibilityDissolution Desirability 1 1 0.75 42.69 1.22 21.1 14 0.558

The selected setting number 1 was used as the dry granulation processand its products were further evaluated. The crystalline structure ofsildenafil citrate in the tablets was studied using Fourier TransformInfrared Spectroscopy (FT-IR). Mid-infrared spectral analysis wasconducted on an FT-IR bench (Agilent Technologies Cary 660, Santa Clara,Calif.). The FT-IR bench was equipped with an ATR (Pike TechnologiesMIRacle ATR, Madison, Wis.), which was fitted with a single bouncediamond coated ZnSe internal reflection element. The spectra werecollected over a range of 4000-650 cm-1. Spectral analysis was conductedusing the Resolutions Pro software suite (Agilent Technologies, CA.).

FT-IR spectral analysis (FIG. 4 ) showed that the amorphous phase ofsildenafil citrate exhibited shifted, shorter and broader spectral bandsrelative to the crystalline phase. This allowed confirmation that thesildenafil citrate's crystalline structure was preserved in the tablets.

Scanning Electron Microscopy (SEM) was used to assess the surfacemorphology of three samples: the powder mixture, melt extruded granules,and the dry granules extruded from the powder mixture. Prior to samplemounting, the surfaces of the samples were cut with a razor in order toprovide a flat surface. These samples were sputter coated with goldunder an argon atmosphere using a Hummer 6.2 Sputter Coater (LaddResearch Industries, Williston, Vt., US) under a high-vacuum evaporatorequipped with an omni-rotary stage tray to help ensure uniform coating.The images were captured at multiple magnifications using a JSM-5600scanning electron microscope (JEOL USA, Inc., Waterford, Va., US) at anaccelerating voltage of 5 kV.

Example 2: Dry Granulation of Ondansetron

This example used ondansetron (OND) as an example of a heat-labilepharmaceutical compound in the dry granulation process. OND is aserotonin 5-HT3 receptor antagonist for treating and preventing nauseaand vomiting induced by chemotherapy/radiotherapy/cancer surgery. ONDexists in a dihydrate form and is susceptible to dehydration whenexposed to heat. This example examined the dehydration behavior of ONDduring the twin-screw dry granulation process.

The materials used in this example were OND (i.e., Ondansetron HCldihydrate) purchased from Chemscene LLC (New Jersey, USA),hydroxyl-propyl cellulose (Klucel™ EF) from Ashland SpecialtyIngredients (Wilmington, Del.), ethyl cellulose (Ethocel Standard 10)from Dow chemical company. All other reagents were analytical grade.

20 wt. % OND, 79.5 wt. % polymers with ethyl cellulose (EC) andhydroxyl-propyl cellulose (HPC) in a ratio of 1:1 and 0.5 wt. %magnesium stearate were first individually passed through a US #35 meshto remove aggregates. The sieved ingredients were then thoroughly mixedto prepare a powder mixture using a V-shell blender (GlobePharma,Maxiblend™ New Brunswick, N.J.) for 20 min at 25 rpm. The preparedpowder mixture was fed into a co-rotating twin-screw extruder (11 mmProcess 11™, Thermo-Fisher Scientific Karlsruhe, Germany) using avolumetric feeder.

Dry granulation was performed using the screw configuration, screwspeed, and barrel temperatures shown in Tables 8 and 9. One screwconfiguration had no mixing zone (configuration 1), the secondconfiguration containing one mixing element along with the conveyingelements (configuration 2) and the third configuration containing twomixing elements along with the conveying elements (configuration 3)(FIG. 5 ). The produced dry granules were then characterized to evaluatethe solid-state phase transformation of OND.

TABLE 8 Dry Granulation Parameters Barrel temperatures (° C.) in zonesScrew Feed Screw of the screw barrel speed rate Config. Feed 2 3 4 5 6 78 Die (rpm) (g/hr) 1 N/A 140 140 140 140 50 50 50 40 25 or 100 80 2 N/A110 110 110 110 50 50 50 40 25 or 100 80 3 N/A  90  90  90  90 50 50 5040 25 or 100 80

TABLE 9 Dry Granulation Batches and Parameters Screw Highest barrelScrew Batch # Configuration temp (° C.) speed (rpm) A1  3 90 100 A2  390 25 A3  3 110 100 A4  3 110 25 A5  3 140 100 A6  3 140 25 A7  1 90 25A8  1 90 100 A9  1 110 25 A10 1 110 100 A11 1 140 25 A12 1 140 100 A13 290 25 A14 2 90 100 A15 2 110 25 A16 2 110 100 A17 2 140 25 A18 2 140 100

Diamond differential scanning calorimetry (DSC, Perkin Elmer Life andAnalytical Sciences, Waltham, Mass., USA) was used to study the phasetransformation of OND as 3-5 mg of pure OND, as a powder mixture ofOND/polymers, and as granules produced by dry granulation. These sampleswere weighed and hermetically sealed in aluminum pans. Thermal analysesof the samples were performed over a temperature range of 25-250° C. ata heating rate of 10° C./min under an inert nitrogen atmosphere at aflow rate of 20 mL/min. Endothermic onset and peak temperature ofmelting were calculated from the obtained thermogram using Pyris™Manager software (PerkinElmer Life and Analytical Sciences, 719Bridgeport Ave., CT, USA).

The effects of screw configuration on OND phase transformation are shownin FIG. 6 . OND-polymer/powder granulated using screw configuration 1exhibited the characteristic melting peak of OND at 189° C., which wasthe same as the powder mixture corresponding to the OND dihydrate form.Using screw configuration 2, the melting peak shifted from 189° C. to179° C. and there was a new endothermic peak at 214° C. When screwconfiguration 3 was used the endothermic peak corresponding to thedihydrate form shifted to a lower temperature (at 169° C.) and a newendothermic peak of the dehydrated form was observed at 223° C.Therefore, the increased number of mixing elements on the screw resultedin more intense mixing and higher shear being exerted on the powdermixture in the screw barrel.

In the dry granulation process, two factors were responsible forgranulating the powder mixture: thermal energy from the heated barreland applied shear mechanical energy. It was also observed that anincrease in the number of mixing elements on the screws (and thus acorresponding increase in applied shearing energy) caused furtherdehydration of OND HCl-2H20. The effects of screw barrel temperature onOND phase transformation are shown in FIG. 7 . The DSC results showedthat there was no shift in the melting peak of OND at low granulationbarrel temperatures when screw configuration 1 was utilized, but at highbarrel temperatures a new endothermic peak appeared at 219° C.corresponding to a peak of dehydrated OND. Using screw configuration 3at a high barrel temperature, only one endothermic peak was observed at217° C., which confirms that the OND had undergone complete dehydration.

Twin screw technology can be utilized for continuous high shear drygranulation. It can achieve the desired level of mixing by a combinationof the appropriate screw configuration and a suitable set of processsettings (e.g. feed rate, screw speed, etc.), thereby producing acertain granule size and shape distribution. In this process, plasticdeformation of the powders can be induced to facilitate bonding into acompact for subsequent milling into granules. Powders can be confinedwithin the particular screw configuration design and as such, subjectedto a compressive stress can rearrange until there is insufficient freevolume to allow translation of particles. As the stress increases,particles can make contacts which increase in areas with stress. Theycan deform elastically (i.e. reversibly) with Young's modulus as thelinear proportionality constant. This process is also known asconsolidation. Consolidation can be described as the increase in themechanical strength of a material as a result of particle/particleinteractions. When the surfaces of two particles approach each otherclosely enough (e.g. at a separation of less than 50 nm), their freesurface energies can result in a strong attractive force through aprocess known as cold welding. This can be major reason why themechanical strength of a bed of powder increases when subjected torising compressive forces within the twin screw extruder.

The effects of screw speed on OND phase transformation are shown in FIG.8 . The granules were prepared using both high and low screw speeds at alow barrel temperature. For both screw speeds, the melting endothermicpeak of OND was 190° C., indicating that screw speed did notsignificantly affect OND dehydration.

Thermogravimetric analysis (TGA) was used to determine weight loss ofOND due to dehydration. A weighed sample of OND was heated from 25° C.to 300° C. at a rate of 20° C./min in a platinum pan under an inertnitrogen atmosphere purge flowing at a rate of 20 ml per minute. The TGAthermogram of OND is presented in FIG. 9 . Heating caused loss of 2moles of loosely bound water from each mole of OND dihydrate. As shownin FIG. 9 , about 10% of the weight was lost when OND was heated from60-105° C., which was in agreement with the theoretical value for 2moles of water per mole of OND.

Dynamic vapor sorption (DVS) was then used to measure the weight loss ofOND during an isotherm dehydration study. The DVS apparatus (SurfaceMeasurement Systems, London, UK) was a commercially available watersorption apparatus, which allowed an OND sample to be weighed underdefined temperature and humidity conditions. About 14 mg of OND wasweighed onto an aluminum pan. The DVS apparatus was programmed to runfrom 0% to 90% relative humidity (RH) at increments of 10% RH and thenagain going from 90% back to 0% RH at decrements of 10% RH. The studywas conducted at 25° C. and in triplicate. The accuracy of the DVSapparatus was ±1.0% for the RH and ±0.2° C. for the temperature.

The DVS mass plot and the drying curve of OND are shown in FIGS. 10 and11 , respectively. The DVS mass plot showed a weight loss of 9.5% at 0%RH corresponding to the loss of two water molecules by dehydration ofeach OND molecule. As the RH increased from 0% to 10% and then to 20%,there was a 2.67% and 8.9% weight gain observed, respectively. There wasonly a very slight weight gain (from 8.9% to 9.2%) when the RH wasincreased beyond 20% up to 90%. Reversing the process, therebydecreasing RH from 90% to 20% only caused a slight weight loss for OND.At 10% RH, the dihydrate form of OND started to lose water and itsweight decreased by up to 4.44%, corresponding to losing one watermolecule per OND molecule. When humidity was further decreased, a rapiddecrease in the water content of the OND was observed, indicating theloss of the second water molecule of the OND at or near 0% RH.

Hot-stage microscopy (HSM) was used to capture images at differentstages of OND transformation. A glass slide with a sample of a smallamount of OND dispersed in silicone oil was inserted into a hot-stagesystem (FTIR 600, Linkam Scientific Instruments, Surrey, UK). The ONDsample was examined while being heated from 35° C. to 150° C. at aconstant rate of 2° C./min. A camera-mounted optical microscope (Cary620 IR, Agilent Technologies, Santa Clara, Calif., USA) equipped with ahot-stage was used to capture images at different stages of the ONDtransformation.

HSM images are presented in FIG. 12 . These images revealed that ONDcrystals started dehydration at a temperature of 90° C. and startedmelting at a temperature of 192° C. These HSM observations correlatedwell with the TGA thermogram where the dehydration event was observed attemperatures in the range of 60-105° C.

Inverse Gas chromatography-Surface Energy analysis (IGC-SEA) techniquewas used for characterizing surface and bulk properties of granules fromtwin screw dry granulation example above. The IGC-SEA is based oninverse gas chromatography (IGC) methodology and is a gas phasetechnique for characterizing surface and bulk properties of solidmaterials. The principles of IGC are simple, being the reverse of aconventional gas chromatographic (GC) experiment. A cylindrical columnis uniformly packed with the solid material of interest, typically apowder, fibre, or film. A pulse of constant concentration of gas is theninjected down the column at a fixed carrier gas flow rate, and the timetaken for the pulse or concentration front to elute down the column ismeasured by a detector. A series of IGC measurements with different gasphase probe molecules then allows access to a wide range ofphyisco-chemical properties of the solid sample.

The injected gas molecules passing over the material adsorb on thesurface with a partition coefficient k_(s):K _(s) =v _(n) /w _(s)Where vn is the net retention volume—the volume of carrier gas requiredto elute the injection through the column, and wS is the mass of thesample. Vn is a measure of how strongly the probe gas interacts with thesolid sample and is the fundamental data obtained from an IGCexperiment. From it a wide range of surface and bulk properties can becalculated. The injection manifold system can GENERATE accurate solventpulse sizes across a large concentration range, resulting in isothermsat high and low sample surface coverages. This can allow for thedetermination of surface energy heterogeneity distributions. The surfaceenergy distribution is the integration of the surface energy profileacross the entire range at surface coverage and is analogous inprinciple to a particle size distribution. The above formulation wassubjected to various barrel temperatures as per table below and at ascrew speed of 100 rpm and a feed rate of 38 g/hr.

Barrel temperature Sample ZONE 2 Z3 Z4 Z5 Z6 Z7 F1 50 50 60 70 60 50 F270 70 80 90 80 70 F2-F3 intermediate 80 80 90 100 90 80 F3 90 90 100 110100 90 F4 120 120 130 140 130 120 F5 140 140 150 160 150 140

The lower surface energy materials would be expected to have a lowerdegree of interaction with components in a blend. As per FIG. 19 ,physical mixture and samples F1 & F2 granulated at much lowertemperatures show very low & constant surface energy profile over thesurface coverage area. However, the total surface energy increases asthe barrel temperature increases from sample F3 onwards. Sample F3 has amoderate surface energy profile as compared to high energy profile ofsamples F4 & F5. Samples F4 & F5 are also deemed as energeticallyanisotropic, i.e., they have regions of different surface energy. Thisis not favorable for granules as it can lead to the powder with varyingbulk properties. However a stable & higher surface energy profile ofsample F3 indicates that surface energy heterogeneity is much less thanthe other samples leading to granules with consistent physicalproperties. By principle, if a solid sample has high surface energy, itssurface molecules are in a high-energy state and it is energeticallyfavorable for them to form strong intermolecular bonds thus leading tobetter agglomeration of the powder. This indicates that the drygranulation formulations manufactured by twin screw technology has muchhigher energy than those created at lower shear values & temperatures.

Example 3: Extended Release Ondansetron (OND) Tablets

The materials used in this example were ondansetron HCl dihydratepurchased from Chemscene LLC (New Jersey, USA), hydroxypropyl cellulose(Klucel EF) from Ashland Specialty Ingredients (Wilmington, Del.), andethyl cellulose (Ethocel Standard 10) from Dow Chemical Company. Fumaricacid and magnesium stearate were purchased from Spectrum LaboratoryProducts Inc. (Gardena, Calif.).

Differential scanning calorimetry (Diamond DSC, Perkin Elmer Life andAnalytical Sciences, 710 Bridgeport Ave., Connecticut, USA) equippedwith Pyris manager software (Shelton, Conn., USA) and Fourier transforminfrared spectroscopy (FTIR, Agilent Technologies Cary 660, Santa Clara,Calif.) were used to study the compatibility of OND with variouspolymeric carriers in 1:1 ratio in a dry granulation process carried outin a twin-screw extruder to provide granules used to produce extendedrelease tablets.

Samples were prepared by hermetically sealing approximately 3-5 mg ofpure OND or powder mixture in aluminum pans, which were then heated overa temperature range of 40-250° C. at a linear heating rate of 10° C./minunder an inert nitrogen atmosphere. An FTIR bench equipped with aMIRacle® attenuated total reflection (Pike Technologies, Madison, Wis.)was used to generate mid-infrared spectra in the range of 4000-650 cm-1,which was fitted with a single bounce diamond coated ZnSe internalreflection element.

The selected DSC curves of the OND and powder mixture are shown in FIG.13 . The DSC curves show a typical melting point endothermic peak ofpure OND in the range of 185.2-188.58° C. The DSC curves also indicatethat OND was compatible with the tested polymeric carriers because therewas no change in the glass transition temperature or melting endothermswhen different polymeric carriers were used in the powder mixture. Thisobservation was further confirmed by FTIR, which showed no change in theinfrared spectrum of the OND when mixed with different polymericcarriers.

The dry granulation process was performed using the formulations andgranulation parameters shown in Tables 10 and 11, respectively.Intragranular magnesium stearate was added to the powder mixture forproducing the granules and extragranular magnesium stearate was added tothe formed granules for producing the tablets. OND and polymericcarriers were passed through US mesh #35 (500 μM) in order to removeaggregates. Fumaric acid was added to the formulations prior tocompression to increase the pH-dependent solubility of the OND.Magnesium stearate was also added to the formulations as a powderlubricant. Further, the powder mixture of OND (about 20 wt. %) andpolymeric carriers (about 79%), with a minor amount of lubricant, wasproduced using a V-shell blender (GlobePharma, Maxiblend™ New Brunswick,N.J.) at 25 rpm for 20 min. Dry granulation was performed without anextrusion die block in a fully intermeshing co-rotating twin-screwextruder (11 mm Process 11™ Thermo Fisher Scientific) with modifiedscrew configurations (FIG. 5 ). The powder mixture was fed to theextruder by a volumetric feeder and the zone adjacent to the feeder wasnot heated (Table 11).

Barrel temperatures for all screw barrel zones are shown in Table 11.The powder feed rate (g/min) and the screw speed (rpm) were each set attwo levels, low and high. As soon as the twin-screw extruder reached asteady state, the granules were collected at the outlet of the extruder.The collected granules were stored in sealed aluminum pockets forfurther analysis.

TABLE 10 Granulation Formulations Formulations OND (%) EC (%) HPC (%)Fumaric acid (%) Magnesium stearate (%) A 20% 36.25% 36.25% 7.5% 0.2%intragranular plus 0.3% extragranular B 20%  37.5%  37.5%   5% 0.2%intragranular plus 0.3% extragranular C 20% 38.75% 38.75% 2.5% 0.2%intragranular plus 0.3% extragranular

TABLE 11 Screw barrel temperatures Barrel Temperature (° C.) Feed ZoneZone Zone Zone Zone Zone 2 3 4 5 6 Zone 7 Zone 8 Discharge N/A 70 70 8090 80 70 70 40

Different screw configurations (FIG. 5 ) were used in the twin-screwextruder to produce dry granules. Screw Configuration 1 resulted inabout 20% granules and about 80% of fine powder, even with the screwbarrel at a high barrel temperature. Screw Configuration 2 resulted inmore granules and less fine powder. Screw Configuration 3 producedsignificant amounts of granulated particles and the granules had arubbery texture, which was hard to break while passing through a sieve.Screw Configuration 2 produced the best quality granules and particlesize distribution, with around 89% of the granules falling within thedesired particle size range (500 μm-1.4 mm).

Different barrel temperatures were used with the various screwconfigurations 1-3 for dry granulation of a powder mixture with OND andpolymeric carrier. Digital images of the granules prepared withdifferent screw configurations and at different barrel temperatures areshown in FIG. 14 . It was observed that a barrel temperatures in therange of 70-90° C. showed promising results without melting of thepolymers. Further, the screw configuration with one mixing elementproduced mostly medium sized granules. Therefore, a combination of screwconfiguration 2 and a barrel temperature in the range of 70-90° C. wasselected for further testing.

Polymeric carriers were employed at either 1:1 or 3:1 ratios of EC toHPC. A 1:1 ratio of EC and HPC provided a larger percentage of mediumsized granules and was selected for further tests.

The granules were compressed into tablets with or without addition of anorganic acid. The tablets without organic acid were unable to releaseOND in intestinal pH media due to its weakly basic nature. An organicacid would solubilize OND in a high pH dissolution medium correspondingto an intestinal pH. Among citric acid, adipic acid and fumaric acid,fumaric acid showed the most promise as it was able to release 100% ofthe drug at an intestinal pH. Magnesium stearate was also added to thegranules at 0.2% as a powder lubricant for the tableting step.

Ten batches of granules were made by the dry granulation process in atwin-screw extruder using 10 different granulation settings. Yields ofthe dry granulation process were found to be high (97-99%). Neither thepolymeric carriers nor the OND melted during dry granulation using theseparameters. No sticking material was observed inside the screw barrelwalls or the screws.

The crystallinity of OND in the granules was compared to pure OND usinga DSC curve for pure OND which showed a melting endothermic peak at 189°C. For all batches Z1-Z10, an endothermic peak was observed in the rangeof 185-191° C. Thus, the crystalline structure of OND was preserved inthe granules.

The particle size distribution of the granules was studied using a sieveanalysis method. Two USA standard test sieves, #35 (500 μm) and #14 (1.4mm) were used and the amount of granules retained on each sieve wasweighed. Three fractions were collected and weighed, one larger than 1.4mm, a medium size between 1.4 mm and 500 μm and un-granulated fines witha size less than 500 μm. The percentile weight distribution wasdetermined (Table 12). For tableting, the medium sized granules were themost important fraction and were used along with 10-15% fines in orderto provide the desired compressibility. Thus, the dry granulationparameters were selected to obtain the maximum percentage of granules ofmedium size. For further testing, the production of granules having asize between 1.4 mm and 500 μm was selected as the sole dependentvariable (response) in the 2³ factorial model,

TABLE 12 Characterization of Granules/Tablets Large Medium Hausner'sCarr's Angle of 100% Drug Batch granules (%) granules % Fines % RatioIndex Repose Release (h) Z1 40.77381 53.21621 6.009985 1.09  8.69 34 6.5 Z2 26.04511 65.20301 8.75188 1.22 18.18 36  6.5 Z3 70.39839 24.64834.953304 1.13 11.53 33  7.5 Z4 81.45596 14.66561 3.878434 1.08  8 43 7.5 Z5 46.61275 48.99556 4.391686 1.13 11.53 30  9.5 Z6 37.4088957.97194 4.619169 1.13 11.53 31 10.5 Z7 37.91596 57.76051 4.323537 1.1311.53 36  9.5 Z8  5.575453 89.6525 4.772045 1  0 25 15.5 Z9 46.10149.33976 4.559243 1.22 18.51 31 12.5 Z10 28.5657 68.91675 2.517553 1.04 4 27 15.5where A, B and C are the screw speed, feed rate, and amount of fumaricacid added to the powder blend prior to extrusion, respectively. Apositive or negative sign of the polynomial term indicates an increaseor decrease in the effect on the granule size by the independentvariables. All three factors had a significant effect on the granulesize, with feed rate producing the most significant effect. An increasein feed rate caused a decrease in the percentage of medium sizedgranules. The highest percentage of medium size granules were obtainedat lower feed rate.

Screw speed was also found to have a significant influence on granulesize since increasing the screw speed from 25 to 100 rpm resulted in anincrease in the percentage of medium sized granules regardless theamount of fumaric acid. Higher fumaric acid contents in the formulationgave a lower percentage of medium sized granules. Hence, the drygranulation process should be conducted at a low feed rate, high screwspeed, and with a low amount of fumaric acid.

The bulk volume (V_(o)) of 5 g of granules was measured in a 10 ml ofgraduated glass cylinder. The bulk density (ρ_(b)) was calculated by thefollowing equation:

$\begin{matrix}{{{Bulk}{density}\left( \rho_{b} \right)} = \frac{{amount}{of}{granules}{weighed}\left( {5g} \right)}{{bulk}{volume}\left( V_{o} \right)}} & {{Eq}.2}\end{matrix}$

The graduated glass cylinder was tapped manually 100 times until nofurther reduction in the volume of the granules was observed. Tappeddensity (ρ_(t)) was calculated by using the following equation:

$\begin{matrix}{{{Tapped}{density}\left( \rho_{t} \right)} = \frac{{amount}{of}{granules}{weighed}\left( {5g} \right)}{{tapped}{volume}\left( V_{100} \right)}} & {{Eq}.3}\end{matrix}$

Carr's (compressibility) index (CI) and Hausner's ratio (HR) werecalculated by the following equations:

$\begin{matrix}{{CI} = {\frac{\left( {P_{t} - P_{b}} \right)}{P_{t}} \times 100}} & {{Eq}.4}\end{matrix}$ $\begin{matrix}{{HR} = \frac{P_{t}}{P_{b}}} & {{Eq}.5}\end{matrix}$

The angle of repose for the granules was determined by the funnelmethod. A funnel was placed above a horizontal plane surface on which awax paper was placed. The accurately weighed granules were freely pouredthrough the funnel onto the wax paper. The height of the funnel abovethe horizontal plane surface was adjusted in such a way that the tip ofthe formed cone of the granules just touched the tip of the funnel. Thediameter and height of the cone were measured and the angle of repose(0) was calculated by the following equation:

$\begin{matrix}{{{Tan}(\theta)} = \frac{h}{r}} & {{Eq}.6}\end{matrix}$where, ‘h’ and ‘r’ are the height and radius of the formed cone ofgranules, respectively.

Flow properties of the granules were important to mixing, die fillingand tableting of the granules, and thus may significantly affect dosageuniformity, content and tablet mechanical characteristics. A Hausner'sratio less than 1.25 or a Carr's index below 15 was considered anindication of good flowability. All of the batches Z1-Z10 had aHausner's ratio value be:pw of 1.25 (Table 12). All the batches had aCarr's index value of less than 15 except batches Z2 and Z9 (Table 19).An angle of repose in the range of 25 to 30 indicated excellent flowproperties. Batches Z5, Z8 and Z10 had an angle of repose of <30. Otherbatches showed angle of repose greater than 30 (Table 12).

Based on the 2³ factorial model, screw speed and feed rate were found tobe the most significant factors affecting the flowability of thegranules. A polynomial regression equation was used to represent therelationship between flowability and the granulation parameters.Angle of Repose=+32.60−3.37*A+2.63*B+1.12*AB−1.38*AC−2.37*ABC  Eq. 12

The screw speed (A) had the most significant effect on angle of reposeof the granules. An increase in screw speed caused a decrease in theangle of repose. An increase in the feed rate (B) caused an increase inthe angle of repose. These observations were well correlated with theparticle size distributions of the granules. A high screw speed and lowfeed rate produced a higher percentage of medium sized granules, whichhad an improved flowability and a lower angle of repose. The correlationamong these granulation parameters and the angle of repose of thegranules is represented in a contour plot and a response surface graph(FIG. 15 ).

The true density of the granules was measured (n=3) with the help of ahelium pycnometer (AccuPyc II 1340 Pycnometer, Micromeritics, USA). Thesurface area of the granules was determined (n=3) using a Gemini VII2390 (Micromeritisc, USA). The true density and surface area of granulesare presented in Table 13.

TABLE 13 True Density and Surface Area of Granules Batch True densitySurface area (m2/g) Z1 1.2419 ± 0.0013 0.2747 ± 0.0021 Z2 1.2421 ±0.0024 0.2015 ± 0.0046 Z3 1.2490 ± 0.0014 0.2804 ± 0.0023 Z4 1.2643 ±0.0011 0.1717 ± 0.0023 Z5 1.2801 ± 0.0012 0.3347 ± 0.0080 Z6 1.2786 ±0.0013 0.1278 ± 0.0034 Z7 1.2227 ± 0.0017 0.3579 ± 0.0093 Z8 1.2246 ±0.0055 0.3239 ± 0.0079 Z9 1.2163 ± 0.0014 0.3904 ± 0.0094  Z10 1.2185 ±0.0008 0.2565 ± 0.0061

The produced granules were mixed with 0.3% magnesium stearate just priorto being fed to a single punch tablet press (MCTMI, GlobePharma Inc.,New Brunswick, N.J.), which used an 8 mm flat round punch at acompression force of 140 kg/cm. Ten tablets were randomly selected fortesting with a Schleuniger-hardness tester. The thickness of the tabletswas measured by a digital Vernier caliper (Montata). The tabletfriability was determined using a dual scooping projection Vander Kampfriabilator (Vankel Industries Inc., Chatham, N.J.) rotating at speed of25 rpm for 4 min. The tablet friability was expressed as the percentageweight loss of the tablets (weighed 6.5 g) after the dual scoopingprojection test.

For drug content uniformity, tablets were accurately weighed and theaverage weight was calculated. The tablets were ground with a mortar andpestle, and powder equivalent to 10 mg of OND was accurately weighed anddissolved in 0.1 N HCl. The absorbance was measured at λ_(max) 305 nmusing a UV-VIS Spectrophotometer and the percentage drug content wascalculated using a calibration curve for OND.

It was observed that all of the produced tablets (from granules ofbatches Z1-Z10) had a uniform weight, thickness, and hardness. Theaverage percentage deviation among tablets of each batch was less than±5%. Hence all batches passed the test for uniformity of weight as perthe USP official requirements.

In-vitro drug release from the tablets was measured using a USPdissolution apparatus type-II (Hanson SR8 Plus), set at a paddle speedof 50 rpm and equipped with UV-Vis probes (Rainbow dissolution monitor,PION). The UV spectra of the dissolution media were collected at λ_(max)305 nm every 2 min for the first 2 h and then every 25 min until 24 h.For the first 2 hours of the dissolution test, the dissolution media (pH1.2) consisted of 700 ml of 0.1 N HCl with 1% sodium lauryl sulfate(SLS). At the 2 hour point, 200 ml of 0.2 M tribasic sodium phosphate(pH 12.5) with 1% SLS (maintained at 37±0.5° C.) was added to achieveand maintain a final pH of 6.8 for the dissolution media. This was forsimulating transit of the tablet from the stomach (pH 1.2, first 2hours) to the intestine (pH 6.8, next 22 hours). An in vitro drugrelease study was performed in triplicate and the mean % drug releasewas plotted versus the time in hours (FIG. 16 ).

The equation derived by employing a best fit mathematical model for thedissolution time based on the granulation parameters was:Dissolution time=+10.10+3.13*A−0.88*B+0.38*C−1.38*AB+0.38*BC  Eq. 13

The screw speed (A) was the dominant factor affecting the drug releaseprofile and tablets produced using a higher screw speed had a longerdissolution time. A negative interaction was observed for AB which had asignificant negative effect on the dissolution time. Eq. 13 is presentedin the form of a contour plot and response surface graph to visualizethe effect of all changing independent variables on dissolution time(FIG. 17 ).

The in-vitro drug release dissolution data for 30 mg OND tablets wasevaluated kinetically by using the following equations includingzero-order, first-order, Higuchi and Korsmeyer-Peppas:

$\begin{matrix}{{{Zero} - {order}{equation}:}{Q_{t} = {Q_{0} + {K_{0}t}}}} & {{Eq}.7}\end{matrix}$ $\begin{matrix}{{{First} - {order}{equation}:}{{\log Q_{t}} = {{\log Q_{0}} + \frac{K_{1}t}{2.303}}}} & {{Eq}.8}\end{matrix}$ $\begin{matrix}{{{Higuchi}{equation}:}{Q_{t} = {K_{H}\sqrt{t}}}} & {{Eq}.9}\end{matrix}$ $\begin{matrix}{{{Korsmeyer} - {Peppas}{equation}:}{\frac{Q_{t}}{Q_{00}} = {K_{kp}t^{n}}}} & {{Eq}.10}\end{matrix}$where, Q_(t) is the amount of drug released in time t, Qo is the initialamount of the drug in the solution (most of the time Q₀=0), Q_(oo) isthe amount of drug released after infinite time, K₀ is the zero orderrelease rate constant, K₁ is the first order release rate constant,K_(H) is the Higuchi diffusion rate constant, K_(kp) is the kineticrelease constant incorporating structural and geometricalcharacteristics of the tablets and ‘n’ is the diffusion coefficientindicating the drug release mechanism, which is dependent on the valueof ‘n’.

As shown in Table 14, kinetic modeling of the release data for all ofthe batches was fitted to the Korsmeyer-Peppas model. The diffusioncoefficient (n) for tablets with granules from all of the batches werewithin the range of 0.59-0.72, indicating a non-Fickian diffusionmechanism and that drug release was governed by both diffusion andmatrix erosion.

TABLE 14 Drug Release Kinetics Zero Order First order Higuchi Korsmeyerpeppas Batch R² R² R² R² n Z1 0.9509 0.9444 0.991 0.9995 0.75 Z2 0.94810.878 0.9878 0.999  0.72 Z3 0.9342 0.9708 0.9818 0.9993 0.69 Z4 0.91390.9808 0.979 0.9983 0.70 Z5 0.9168 0.8568 0.9822 0.9993 0.63 Z6 0.8940.9066 0.9777 0.9973 0.62 Z7 0.947 0.8014 0.9843 0.9985 0.58 Z8 0.9190.8323 0.9926 0.9982 0.59 Z9 0.9151 0.9754 0.9761 0.9986 0.63  Z100.9433 0.9011 0.9988 0.9997 0.62

To achieve the combination of a high percentage of medium sized granulesand the desired dissolution time required for attaining complete andextended drug release from the tablets, with a low angle of repose forthe granules, a desirability plot was generated to understand therelationship between granulation parameters and the quality values (FIG.18 ). Specifically, the produced granules should have good flowproperties (a lower angle of repose with value within 25-31), a higherpercentage of medium sized granules (70-90%) and more time should berequired for dissolution of the dosage (a release time of 12-16 hours).The calculated desirability value for the batch Z8 is 0.880 whichindicated suitability of the designed factorial model.

This application discloses several numerical ranges in the text andfigures. The numerical ranges disclosed inherently support any range orvalue within the disclosed numerical ranges, including the endpoints,even though a precise range limitation is not stated verbatim in thespecification because this disclosure can be practiced throughout thedisclosed numerical ranges.

It is to be understood, however, that even though numerouscharacteristics and advantages of the present disclosure have been setforth in the foregoing description, together with details of thestructure and function of the disclosure, the disclosure is illustrativeonly, and changes may be made in detail, especially in matters of shape,size and arrangement of parts within the principles of the disclosure tothe full extent indicated by the broad general meanings of the terms inwhich the appended claims are expressed. Finally, the entire disclosureof the patents and publications referred in this application are herebyincorporated herein by reference.

The invention claimed is:
 1. A granule produced by the methodcomprising: mixing a first powder comprising at least one activeingredient having a crystal structure and a second powder comprising atleast one carrier to form a powder mixture; feeding the powder mixtureto a twin-screw extruder without a solvent, liquid binder, or meltablebinder; kneading the powder mixture in a heated screw barrel of thetwin-screw extruder, wherein all temperatures along the length of thescrew barrel are below a melting point of the at least one activeingredient and below a melting point or a glass transition temperatureof the at least one carrier to form a kneaded powder mixture; andextruding the kneaded powder mixture to form the granule, wherein thegranule is free of solvents, liquid binders, and meltable binders, has asurface area of about 0.05-0.45, has an angle of repose of less than orequal to about 30, and the crystal structure of the at least one activeingredient is preserved in the granule.
 2. A granule comprising: atleast one active ingredient having a crystal structure and at least onecarrier having a melting point or a glass transition temperature lowerthan a melting point of the at least one active ingredient, wherein thegranule is free of solvents, liquid binders, and meltable binders, has acompressibility index of about 10-30, a Hausner ratio of less than about1.25, a surface area of about 0.05-0.45, and an angle of repose of lessthan or equal to about 30, and the crystal structure of the at least oneactive ingredient is preserved in the granule.
 3. The granule of claim2, wherein the granule has a true density of about 1.15-1.35.
 4. Thegranule of claim 2, wherein the at least one active ingredient isselected from the group consisting of heat-sensitive activepharmaceutical ingredients, dehydration-sensitive active pharmaceuticalingredients, poorly-compressible active pharmaceutical ingredients, andhigh-dosage active pharmaceutical ingredients.
 5. The granule of claim2, wherein the at least one carrier is selected from the groupconsisting of polysaccharides, povidones, acrylates, celluloses andpolyols.
 6. The granule of claim 2, wherein the at least one carrier isselected from the group consisting of homopolymers and copolymers ofN-vinyl pyrrolidone, copolymers of N-vinyl pyrrolidone and vinyl acetateor vinyl propionate; cellulose esters and cellulose ethers,hydroxyalkylcelluloses, hydroxyalkylalkylcelluloses, cellulosephthalates, cellulose succinates; polyethylene oxide, polypropyleneoxide, copolymers of ethylene oxide and propylene oxide; polyacrylates,polymethacrylates, polyacrylamides; vinyl acetate polymers, polyvinylalcohol, oligo- and polysaccharidesand mixtures of one or more thereof.7. The granule of claim 2, wherein the at least one carrier is selectedfrom the group consisting of hydroxylpropylcellulose, ethylcellulose,carboxymethylcellulose, hydroxyethylcellulose, methylcellulose,ethylhydroxyethylcellulose, hydroxyethylmethylcellulose, hydrophobicallymodified hydroxyethylcellulose, hydrophobically modifiedethylhydroxyethylcellulose, carboxymethylhydroxyethylcellulose, andcarboxymethyl hydrophobically modified hydroxyethylcellulose.
 8. Thegranule of claim 2, wherein the at least one carrier is a polymericcarrier having a molecular weight in a range of about 2,000-2,000,000Daltons.
 9. An oral dosage formulation comprising the granule of claim2, wherein the oral dosage formulation is a capsule, pellet, sachet,powder, or tablet.